Drug Discovery

Retinol Vitamin A Family

Vitamin Family Dirivitive

Early work on this vitamin was confusing because similar outcomes were seen with ingestion of yellow vegetables and colorless fish liver oils. It finally was shown that carotene (the yellow pigment) extracts from vegetables were converted to colorless retinal. Because the retinoids are discussed in considerably more detail elsewhere, this chapter presents only a cursory overview of their biochemical functions. . 3.1.1 Chemistry. The commercial form cf vitamin A is all-trans retinol, usually...

II h3c ch2 o

Common Dosage Forms

Roleofbiotinin leucine catabolism. p-aminobenzoate glutamate Folic Acid (FA) Figure 8.47. Common forms of folic acid and methotrexate. Figure 8.47. Common forms of folic acid and methotrexate. The most reduced coenzyme is 5-methyl tetrahydrofolate polyglutamate. It is the source of the methyl group added to homocys-teine regenerating methionine and tetrahy-drofolate ready to accept a one-carbon unit from formate or serine. This last reaction is where folic acid and vitamin B13 come...

Viral Chemokines And Chemokine HbLtHIURS

Drug Chemokine

Herpesviruses, poxviruses, and lentiviruses all encode chemokine and chemokine recep- r-like molecules (347). Some of these molecules are structural homologs of chemokines and chemokine receptors, whereas others are structurally unrelated but bind to either che-okine or receptor and alter the function of these molecules. The selective advantage of expressing these chemokine or chemokine reis not yet clear. However, given that emokines play a crucial role in organizing the host immune response,...

Chemistry and Structure Activity Relationships

Sar Reserpine

Sildenafil (6) is a pyrazolopyrimidinonederiv-ative. The pyazolopyrimidinone ring is essential for PDE5 inhibitory activity. It seems that this ring structure mimics the guanosine base of cGMP (149). Another ring system that has been shown to produce potent and selective PDE5 inhibitory activity is imidazoquinazoli- none (150). In the sildenafil series, the n-pro-pyl substitution on position 3 of the pyazolopy-rimidinone ring gives a more potent compound compared with a 3-methyl analog....

Leukotriene Analog Antagonists

Montelukast Sodium Structure

6.1.3.1 SKF 104353 (Pobilukast) and SKF 106203. SKF 104353 (30) (210) and SKF 106203 (31) (211) were both developed by the SK& F group through the sequential modifica- tion of the structure of LTD4 and were the first CysLTl antagonist clinical candidates to be so derived (212). Although SKF 104353 is about 10-fold more potent in vitro than SKF 106203, it has very poor oral bioavailabilitysuch that its clinical development was limited to aerosol formulations. In contrast, SKF 106203 had much...

Identification of Retinoic Acid Target Genes

Target Gene Identification Tool

Clearly, RARs and RXRs bound ligand, and was demonstrated directly as described bove, but these proteins also belong to the iNR superfamily of sequence-specific DNA binding transcription factors. Thus, the next piajor question that required an answer was what is the nature of the DNA response ele-lent to which the RARs and RXRs bind lis was an extremely important question be-ause the answer would provide clues regard- the nature of RA target genes. At the time, Dine response elements for...

Pharmacologically Active Retinoids

Because retinol deficiency results in keratini-zation of epithelial tissue, at one time retinol was recommended for skin conditions including acne. There is no clinical evidence that retinol is effective for skin conditions. Now that it is realized that the active form is retinoic acid, the focus has been on developing pharmacologically active compounds based on this structure. These are divided into treatment of three groups 1 acne, 2 the autoimmune disease psoriasis, and 3 malignancies....

Biological and Therapeutic Functions of Prostanoids

The major roles of prostanoids are in the autocrine and paracrine control of physiological processes, and therapeutically they have found use mainly in obstetrics, gastoenterol-ogy, ophthalmology, and the treatment of cardiovascular disease. In the reproductive system, prostaglandins, especially of the E and F series, have potent effects on uterine contraction and have been used to stimulate abortion, cervical ripening, and the induction of labor (13). In addition, in many laboratory and farm...

CXCR1CXCR2 Peptide Antagonists

Cxcr1 And Cxcr2 And Groa

As indicated above, the chemokine N-termi-nus seems to contain a critical recognition site important for receptor binding and activation. The ELR sequence is essential to CXCRl li-gand interaction and its importance in IL-8 has been established through analog deletion or amino acid substitution within this region (13). Truncation of the first five amino acids in the IL-8 Nt (IL-8 6_72 ), or substitution of the first five amino acids with two alanines (IL-gave high affinity antagonists capable...

Structure Activity Relationships

Tocin and vasopressin are neurohypophyseal hormones synthesized in the hypothalamus and then transported along with their carrier proteins to the posterior lobe of the pituitary gland. They were first discovered in the posterior pituitary gland, but they also are located in the CNS and numerous other organs. These peptides both consist of nine amino acids they both contain a 20-membered disulfide and an acyclic tripeptide tail and the two peptides differ only in positions 3 and 8. Oxytocin...

SAR of Bupropion and Its Analogs

Bupropion (15), also known as amfebuta- mone, is ethyl)amino -l-propane. It is a trimethylated monocyclic phenylaminoketone and is structurally unrelated to the tricyclic antidepres-sants or MAO inhibitors. Commercially available bupropion is a racemic mixture. The two enantiomers were synthesized and assayed for their potencies as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain (212). No significant difference was found. However, the relative pharmacological...

Mechanisms of Action of Sunscreens

Sunscreens delay the induction of sunburn by absorbing or reflecting a portion of the UVR reaching the epidermis. Organic sunscreens are aromatic compounds that absorb light energy in the UV region, and therefore reduce the amount of UVR reaching the stratum cor-neum. A benzene ring has the ability to transform high energy UVR into harmless long wave radiation above the 380-nm range, which is emitted from the skin as heat (294). The conversion of UVR to longer wavelength occurs through...

Prostanoid Receptors Location of Ligand Binding Sites

Misoprostol Prostanoid

Recent advances in molecular biology have meant that the critical regions of amino acids to confer high affinity ligand binding are now beginning to be determined. For example, the importance of arginine at position 329 in the seventh transmembrane domain of all EP receptors has been examined by point mutations in the rabbit EP3 receptor. Thus, mutation of this amino acid to alanine or glutamate abolished the binding of 3H -PGE2, whereas the mutation of aspartate 388 was without effect on...

Ai Drug Discovery

Dexamethasone Methylprednisolone

Infants (0-12 months) Children (1-8 years) Boys (9-18 years) Girls (9-18 years) Men (19-50 years) Women (19-50 years) Men (51-70 years) Women (51-70 years) Men (70+ years) Women (70+ years) Pregnancy Lactation UL Infants Children (1-18 years) Adults (over 19 years) Pregnancy Lactation 5 iug (200 IU) day 5 fig (200 IU) day 5 fig (200 IU) day 5 jag (200 IU) day 5 ftg (200 IU) day 5 jxg (200 IU) day 10 jug (400 IU) day 10 fx g (400 IU) day 15 jug (600 IU) day 15 fig (600 IU) day 5 fig (200 IU) day...

Vitamin Uptake and Metabolism

Is is very complicated and is dependent on e source. From a biochemical viewpoint, it is hormone because, in the presence of ade-ate sunlight, the cholecalciferol is produced m the 7-dehydrocholesterol in the skin. In context D vitamins, when administered in iplements, could be considered replace-ient therapy. When photochemically synthe- ed in the skin, it is transported to the liver aspecific binding protein formed in the skin ere the cytochrome enzyme system hy-ixylates it to...

Selective NSAIDs and NSAIDs Modified for Improved COX2 Selectivity

Indomethacin

Given the homology between the two cy-clooxygenases, the reexamination of known anti-inflammatory agents, with particular interest in reported PGHS inhibitors, is an area of research regenerated by the identification of the inducible COX-2 isoform. Some of the most selective NSAIDs, such as diclofenac, have COX-l COX-2 selectivities in about the threefold range 386 . However, tomexiprole 86 was reported to have 30-fold COX-2 selec- tivity 387 . Surprisingly, etodolac 87 has been reported to be...

X CH2OH CH20CH3 Y Oh Ome

Circuitos Chao Para Escola

R H (I), CH2CH2OH (II), CH2CHOHCH2OMe (III) Two examples given with LD50 values of 17.3 and 16.4 g I kg in mice. II at 350 mg I mL has osmolality 735 mOs kg and viscosity 9.4 cP at 37 C, LD50 1.460 mg I kg in rat. Better than iohexol. Table 10.4 (Continued) Type (Subclass) 11 R1 H R2 CH3 R3 H, CH3 R4 H, CH2CH2OH. III R1 H R2 CH2CH2OH R3 CH3, CH2OH, CH(CH3)OH, CH(OH)CH2OH, CH30CH3 R4 H R3R4 -CH(OH)CH2CH2CH2-. IV R1 H R2 CH2CH(OH)CH2OH R3 CH3, CH2OH, CH(CH3)OH, R4 H. V R1 CH2CH2OH R2...

Synthetic Prostaglandins

Gemeprost is a synthetic analog of PGE,. It is usually given vaginally as and is used therapeutically to soften and dilate the cervix and to stimulate uterine muscle contraction in the termination of pregnancy. For the latter indication, ge meprost may be given intravaginally in conduction with oral mifeprostone 306 .Mifepro-stone is a progesterone antagonist and serves to sensitize the uterus to prostaglandins. This facilitates the use of lower doses of prostaglan-dins in...

Introduction

Cis Retinoic Acid

Retinoids are derivatives of vitamin A that have both diverse and essential actions in developmental and cellular differentiation processes, vision, and reproduction (1). The biological activity of retinoids has been appreciated since the 1920s (2, 3), and the huge strides made by synthetic chemists, and molecular, developmental, and structural biologists since the late 1980s have contributed dramatically to our understanding of the molecular processes that underlie the biological activities of...

Uses of Dietary Reference Intakes

Each type of reference value is calculated from daily intakes averaged over time (usually one or more weeks). The surveys include, but are not limited to, (1)random selection of healthy individuals and asking them to either report what they have eaten or to maintain food diaries, (2) monitoring overall food production and consumption, and (3) correlating a defined population's health status with the group's food intake. Sometimes the results from the surveys...

Biochemical Functions and Deficiency

Two retinoids, retinoic acid and retinal, appear to have most of the biochemical functions attributed to vitamin A. Retinoic acid is required for cell differentiation and is the ligand for two families of nuclear receptors, RAR 7 and RXRa 3 These receptors are part of a family of superreceptors that include the steroid hormones and cholecalciferol. Vitamin A deficiency can lead to a variety of symptoms depending on the age of the deficient person. The most serious syndrome is keratomalacia,...

Future Trends For Otc And Lifestyle Drugs

What will the future of OTC look like Back in the 1990s, Rx-to-OTC switches were deemed to be the driving force for growth in the OTC industry. We did see rapid growth in the mid-1990s, but the number of switches has dwindled substantially near the end of the 20th century (323). The so-called easy ones have been switched. Pharmaceutical companies need to be creative with future switches. Several seemingly promising switches such as the and acyclovir have been denied by the Advisory committee...

What Do The Pills Saviprazole Treat

Sar Benzimidazole

Rabbit gastric < H+ K+) ATPase. 'Porcine gastric (H+ K+) ATPase. dShay rat. eGhosh and Schild rat. Intravenous administration. hances the rate of attack of the C-2 position of the benzimidazole group and thereby promotes the acid-catalyzed rearrangement to the active species. This electronic feature is present in omeprazole (3,5-dimethyl-4-me-thoxy) and pantoprazole (2,3-dimethoxy), whereas it is combined with increased lipophilic character in 4-fluoroalkyl...

Ach MuscarinicReceptor Mediated Acid Secretion

Propantheline Bromide Synthesis

Ach, released after vagal stimulation, binds to muscarinic receptors present on both the acid-secreting parietal cell and the HA-secreting ECL-like cell (Fig. 3.3). Muscarinic receptors stimulate the secretion of acid, pepsinogen, and mucus in the gastric mucosa. Autoradiographic techniques have shown that the M receptor is overexpressed in DU (61) therefore a selective M3-receptor antagonist may provide a useful antisecretory therapy. Muscarinic receptors are currently subdivided into Mx>...

Physiology and Pharmacology

Hair growth goes through a three-phase cycle (74) anagen (growth phase), catagen (involution), and telogen (rest). At the end of the telogen phase, hair is shed and the next cycle begins. In a normal scalp, approximately 90-95 of hair is in the anagen phase. The duration of anagen determines the hair length. Hair diameter is determined by the volume of the hair bulb. The scalp's terminal hair follicles are predetermined to grow long thick hair, whereas the...

Alprostadil Prostaglandin E Alpro

Prostaglandin

Stadil is the name given to an injectable formulation of PGElf which when administered exogenously causes vasodilatation and the inhibition of platelet aggregation. It exerts its actions primarily through EP and IP prostanoid receptors. Th main clinical usesare in the treatment of male erectile dysfunction and congenital heart disease. Alprostadil is largely inactivated by the lungs on its first passage through the pulmonary circulation. Its metabolites are excreted in the urine within...

Physiological Actions of Prostanoids

Prostaglandins have a wide range of actions in normal cell physiology, but also as pathophys-iological agents in, for example, inflammation and pain states. The roles of the natural pro-stanoids are reviewed in this section in relation to studies on receptor distribution, which provide useful information concerning potential pharmacological applications. Recent advances in molecular biology have also allowed the creation of prostanoid receptor knockout mice, which have proved valuable in...

Toxic Effects on Red Blood Cells

Contrast media produce morphological changes of red blood cells by altering their size and shape and also increase their tendencies for aggregation 555, 556 . The change in morphology of red blood cells is caused by chemo-toxicity and hyperosmolality of the contrast medium 557, 558 . The chemotoxic effect affects the red blood cell membrane and transforms the normally biconcave disc-configured red blood cell into a crenated cell known as an echinocyte. Ionic and nonionic contrast media, such as...

Prostaglandin Discovery and the Connection to NSAIDs

Pathophysiology Ndaids

Prostaglandins are the earliest of the eico-I sanoids to be discovered. Originally described y von Euler in the late 1940s as the active principal components in semen that induced Niterine contractility (273), the structures of e most important of these (PGE2, PGF , PGD2) were elucidated in the 1960s by Berg-st rom. Hamberg, Samuelsson, and others (Fig. 5.3) (274). The multiple activities of these substances were the topic of intense research in the 1960s and 1970s, where roles in reproductive,...

Sulfonylphenyl COX2 Class

Cox2 Inflammation

Most investigated area of selective COX-2 inhibitors is the 4-sulfonylphenyl super genus or family, to which both Celebrex (celecoxib)and Vioxx (rofecoxib) belong (325, 326). Often referred to as the tricyclic, diaryl, or cis-stilbene class, the lead structures for this general class were a series of known diaryl antiinflammatory agents. The most referenced lead structure appears to be DuP 697 (49) (327). The development of this compound was in part driven by the observation of less...

Peptide Leukotriene Antagonists of Diversified Structure

Leucortine Antagonist Structure

ONO 1078 (pranlukast, 38) is not a member of either the (38) ONO RS-411, ONO 1078 (pranlukast) FPL-55712- or the leukotriene D4-derivedsets of antagonists. It was developed from a weak lead, compound (19) (IC60 14 iM versus LTD, on guinea pig ileum). Replacement of the benzoic acid group with a chromanone car-boxylic acid (similar to that found in FPL-55712) resulted in an analog that dis played a 150-fold increase in potency in uitro 1(105, 100 nM) and modest...

Peptide and Protein Hormones Peptide Neurotransmitters and Therapeutic Agents

Peptide Drug Discovery

Hruby Catherine Gehrig de Chavez Malcolm Kavarana University of Arizona Department of Chemistry Tucson, Arizona Burger's Medicinal Chemistry and Drug Discovery Sixth Edition, Volume 4 Autocoids, Diagnostics, and Drugs from New Biology Edited by Donald J. Abraham ISBN 0-471-37030-4 2003 John Wiley & Sons, Inc. 3.4 Topographical and Conformational 4.1.1 Structure and Function, 53 4.1.2 Overall View of the Structure of PTH, 54 4.1.3Importance of Ala1 and Val2 in Signal Transduction, 55...

References

Williams, W. Chong, G. Acsadi, A. Jani, and P. L. Feigner, Science, 247, 1465 (1990). 2. M. A Hickman, R. W. Malone, K. Lehmann-Bruinsma, T. R. Sih, D. Knoell, F. C. Szoka, R. Walzem, D. M. Carlson, and J. S. Powell, Hum. Gene Ther, 5,1477 (1994). 3. H. Herweijer, G. Zhang, V. M.' Subbotin, V. Budker, P. Williams, and J. A. Wolff . Gene Med, 3,280(2001). 4. C. H. Miao, A. R. Thompson, K. Loeb, and X. Ye, Mol. Ther., 3,947(2001). 5. M. L. Sikes, B. W. O'MalleyJr.,...

Formation of Retinyl Esters

Retinaldehyde, when bound to retinol binding protein II (CRBPII),serves as a substrate for retinal reductase resulting in the production of retinol (14), which then binds to cellular retinol binding protein (CRBP) forming holo-CRBP. Holo-CRBP seems to be the preferred substrate for an esterification reaction (Fig. 7.6) mediated by lecithin retinol acyl transferase (LRAT), a microsomal enzyme that uses acyl groups donated from phosphatidylcholine (14) .In cells not expressing CRBP,...

Insulin and Hypoglycemic Agents

Sar Sulfonylureas

Mark Sleevi Insmed Incorporated Richmond, Virginia 2 Current Drugs on the Market, 4 2.1.1 Side Effects, Adverse Effects, 5 Absorption, Distribution, Metabolism, and Elimination, 5 2.1.3 Physiology and Pharmacology, 8 2.2.1 Side Effects, Adverse Effects, 15 2.2.2 Absorption, Distribution, Metabolism, and Elimination, 15 2.2.3 Physiology and Pharmacology, 17 2.3 Insulin-Sensitizing Agents, 20 2.3.1.1 Side Effects, Adverse Effects, 21 2.3.1.2 Absorption, Distribution, Metabolism, and Elimination,...

Lonolactone Medicine

Outline of ascorbic acid biosynthesis. Table 8.5 Metabolie Roles of Ascorbic Acid (Vitamin C) 4 - Hydroxyphenyl-pyruvatedioxygenase hydroxylase phenethyl chain Amidate carboxyl end of peptide of proline Posttranslational hydroxylation of lysine Hydroxylation of trimethyl lysine from glucose (Fig. 8.57). The pathway follows the standard route to glucuronic acid. The aldose carbon is reduced to an alcohol and, following normal carbohydrate-naming convention, the former carbon 6 of...

Phosphoribosyl5aminoimidamle4 carboxamide AICAR

5-Phosphoformylribosylglycinamide (FGAR) 5'-Phosphoribosyl -5-formamidoimidazole-4-carboxamide (AlCAR) Figure 8.50. Coenzyme roles for 10-formyl THF. Figure 8.51. Methylation of deoxyuridylic acid forming deoxythymidylic acid. Figure 8.51. Methylation of deoxyuridylic acid forming deoxythymidylic acid. and or an inflamed mucosa inhibits folate transport. Finally, anticonvulsants such as phenytoin somehow interfere with folic acid uptake or utilization. The dihydrofolate reductase inhibitor,...

Niacin Nicotinic Acid Niacinamide Nicotinamide

The history of niacin revolved around trying to find a way to prevent and cure pellegra, the late-stage deficiency disease caused by a niacin deficiency. Pellagra has been a serious nutritional disorder in the United States, mostly in the southeast. Two thousand deaths from pellagra were reported in 1941. This is ironic because nicotinic acid, later known as niacin, was first reported during the structure elucidation of the alkaloid nicotine. Like some of the other deficiency diseases, there...

Pharmacology

Contrast media by necessity are relatively nontoxic. Adverse reactions accompanying their use vary and usually decrease in intensity and complexity in the order intracerebral > intravascular > oral route of administration > topical application (442-457).Contrast molecules that bind proteins, biomacromol-ecules, and enzymes are more toxic than those that do not. The toxicity decreases with increasing hydrophilicity for different classes of contrast media oral cholecystographic media >...

Ethical Considerations

Pharmacogenomics has created a new lexicon that all health care providers must familiarize themselves, and thus precise language is fundamental when dealing with pharmacogenom-It is imperative that pharmacogenomics be distinguished from genetic predisposition testing. All investigators in the field must convey this concept to the public, members of the health care team, and the insurance sector. In the majority of cases, identification of SNPs to predict drug response carries no prognostic...

Phase 1 Advisory Panel Review

The panels were asked to categorize the active ingredients in each class of products and their claims into one of three categories based on review of data submitted by manufacturers, scientific data in the literature, and their own experiences. The three categories (24, 25) are as follows Category I generally recognized to be safe and effective for the claimed indications Category II not generally recognized as safe and effective or unacceptable for the claimed indications Acne Anorectal...

Emergence of Sunscreens The first

Commercial sunscreen product appeared in the United States in 1928. It was an emulsion of benzyl salicylate and benzyl cinnamate. In the early 1930s, a 10 solution of phenyl sa- licylate was developed and marketed in Australia. In 1935, quinine oleate and quinine bisulfate were marketed in the United States. -Aminobenzoic acid (PABA) was patented in 1943, and was for many years the leading organic sunscreen. Several aminobenzoates (PABA derivatives) were introduced subsequently. PABA...

Ring Expanded Analogs of MTII To

Study the bioactive backbone conformations required for tight binding and receptor selectivity at the human melanocortin receptors, a series of ring-expanded MT-II analogs having alanine at position 10 were synthesized (157). Table 2.11 Comparative Biological Activities of Topographically Modified MT-II Analogs3 E(2S, 3S) -jS-Me-Phe7 -MT-II (2S, 3i ) - -Me-Phe 7 -MT-II (2 , SS) - -Me-Phe7 -MT-II (2 , 3 )-j3-Me-Phe7 -MT-II (2S, 3S)- -Me-Trp9 -MT-II (2S, 3fi)-jS-Me-Trp9 -MT-II (2B, 3S)- -Me-Trp9...

CCR5 Small Molecule Antagonists

Retinoic Acid Metabolites

As a consequence of screening, the National Cancer Institute chemical repository for inhibitors of HIV-1 replication, the distamycin analog NSC65106 (42) was identified as having antiviral activity (209). Its mechanism of action appears to be through involvement of chemokine receptors such as CCR5 and CXCR4. It has also been shown to inhibit CCR1 and CCR3 and is inactive against CCR2 and CXCR2 (210). The monomer (43) and re-gioisomer (44)were inactive against this panel of receptors. As part of...

Research And Development

It costs the pharmaceutical industry approximately 880 million and 15 years to go from target identification through regulatory approval for a novel drug. One-half of this cost and time occur during phase II III clinical trials. Contributing to the prodigious cost and time are the many inefficiencies of drug discovery, development, and clinical trials. Seventy-five percent of the costs of drug development are incurred from late-stage clinical trials. Incorporation of...

OH or Cl R NH2 NHAc NAc2 or I R1 NH NHAc NAc2 NHCOPr OMe or I

Q chemical bond, (CH2)2, or OCHEt R OH or CI R1 NH NHAc, NAc2> or I R2 NH2, NHAc, NAc2, NHCOPr, OMe, or I. Q chemical bond, (CH2)2, or OCHEt R CH CC13, Bu, CH2C02Me, or CH2CMe2COMe R1 H, NH2, or NHAc R2 H or CONHMe. X, Y OH or NRR1 with R H, Me, or CH2CHOH R1 H or Me NRR1 morpholino (A residue of an amino acid, e.g., glycine, DL-serine, DL-alanine, sarcosine, proline, or glycyl-L-leucine Z H or COR, with R Ac, COCH2OMe, COBu, or COCH2OH R1 (hydroxyalkyl)amino R2 amino R3 alkyl, hydroxymethyl,...

Structure and SAR of the Proton Pump Inhibitors

Proton Pump Inhibitor Moa With Figure

In 1973 workers at AB Haessle in Sweden, identified timoprazole 118 as one of the first well-defined inhibitors of the newly discovered gastric proton pump. This compound stemmed from efforts to separate the toxicity and acid-inhibitory properties of 2-pyridyl-thioacteamide CMN131 . Removal of the thioamide group was considered to be the most likely solution to the toxicity of CMN131, which prompted the preparation of sulfur-containing heterocycles, as well as imidazo-line- and...

Receptor and Receptor Subtype Selective Retinoids

White Snowflakes Clip Art

As discussed in a previous section, the systemic and topical toxicity, as well as the teratogenicity of retinoids, limits the clinical usefulness of these compounds. The general opinion of both basic scientists and clinicians is that these toxicities may be mitigated by the development of receptor subtype-selective retinoids. Although this may ultimately be proven to be true, there is currently little factual basis for this opinion, at least with respect to the RAR subtypes, because it has been...

Ch2oh ch2oh

Sition of the amide group or the N-acetyl's methyl group with reference to the plane of triiodophenyl ring. The various geometric isomers will coalesce into one form at higher temperature (265). The dimer or bis compound iodixanol has three geometric isomers exo-exo, exo-endo, and endo-endo forms that can be adjusted to elute as a single peak by HPLC for the purpose of quantitation (270).A multiplicity of isomeric forms in nonionic contrast agents is necessary for high water solubility because...

Structure of LipidDNA Complex

Liposome Dna Complex Tumor

Positively charged cationic liposomes electrostatically interact with negatively charged nucleic acid sequences to form fused, aggregated complexes, which are capable of entering a cell. These aggregates have a very heterogeneous distribution with respect to particle size and net charge. The lipid-to-DNA mass and charge ratio, which defines the size and net surface charge of the complex, is an important factor to determine transfection efficiency. Hence, the structural features associated with...

OTC Classification in Japan

Drugs in Japan are classified into prescription, non-prescription (OTC), and quasi-drug. Prescription drugs are those drugs that require physician supervision (50-53). Non-prescrip-drugs are primarily for mild actions and are only available in the pharmacy or drug store. Deregulation reform reclassified 15 categories of non-prescription drugs to create a new class of drugs called quasi-drugs, which can be sold in convenience stores and supermarkets starting in Spring 1999 (51). Quasi-drugs are...

Future Trends

Trazodone Erection

A few dozen potential products are in clinical development for male and or female sexual disorders. Several of these potential products are novel delivery systems of already marketed compounds, such as two topical delivery systems of alprostadil developed by NexMed and Macro Chem, and a lyophilized liposomal delivery system for urethral administration of alprostadil, developed by Harvard Scientific. New oral agents that target central and peripheral pathways of erection are expected t be...

EP Receptor Selective Ligands

Structures of some EP, receptor selective ligands are depicted in Fig. 6.5. To date, no highly selective, potent EPX receptor agonists have been described, and it is only recently that potent EPX receptor antagonists have been reported. 17-phenyltrinor-PGE2 (see above), 16,16-dimethyl PGE2, ICI 80205, and 9-methylene PGE2 all show moderate EPX re ceptor selectivity but are also active at other EP receptors (222). ICI 80205 also has TP receptor activity. Sulprostone was also identified as an EPi...

OTC Classification After OTC Drug

The OTC Drug Review is based on the principle set down in the Durham-Hum phrey amendment that if a drug can be OTC, it should be OTC (23, 30). Prescription status should be an exception. However, the history of drug approval suggests otherwise. Most new chemical entities are initially approved as prescription drugs, which may then be switched after a period of at least 5 years cf marketing experience and meeting certain switch criteria (29). Direct OTC approval of new chemical entity is...

History

Early research on smoking cessation therapy started in the 1930s. The first experimental medication was lobeline, an alkaloid with physiological actions similar to nicotine. Lobeline and other early non-nicotine drugs failed to show any benefits beyond those seen with placebo (170). As a result of poor efficacy of these experimental drugs, researchers started focusing on nicotine. The first U.S. Surgeon General's report on smoking, which was released in 1964 (214), stimulated the research...

Profile of Proton Pump Inhibition

Rabeprazole Eisai

Omeprazole is a potent and irreversible inhibitor of H+ Kt-ATPase. Subsequently developed compounds (lansoprazole, pantoprazole, esomperazole, and rabeprazole) have a similar mechanism of action, although small differences in bioavailability, potency, and metabolism have been reported. Comparative studies with lansoprazole and pantoprazole suggest that they have a potency similar to that of omeprazole (143). Rabepra-zole is readily converted to the active drug form and has a more rapid onset of...

Retinoid Metabolism

Udp Glucuronyl Transferase Deficiency

Tissue-specific catabolism of RA is extremely important in terminating the retinoid signal, and ultimately, in dictating the tissue responsiveness to RA. Thus, the metabolism of RA and related compounds has generated a large amount of interest for both clinicians and basic scientists. Consistent with other aspects of retinoid biology, metabolism of RA and RA precursors is a complex area. First, one of the major pathways of RA metabolism is gluc-uronidation at the carboxyl group (Fig. 7.12)....

Cene Expression and Drug Response

The difference between a compound and an agent is dictated by the cell just as the difference between an agent and a drug is dictated by the patient. However, at this point, we would like to make a simplification of terms in which a compound, an agent, or a drug will merely be referred to as a drug even though a compound or agent may not be of known medical value. The NCI 60 cell lines have been screened for sensitivity to a 70,000 drug library, resulting in a wealth of data for identification...

Bioinformatics Meets Chemoinformatics

The discussions above touch on only the surface of the potential applications of gene expression profiling as applied to drug development. The power of microarray technology and gene expression profiling will likely be further magnified by their interface with other information-intensive tools, such as used in chemoinformatics. For example, quantitative structure-activity relationship (QSAR) models relate the molecular descriptors of drugs to various biological or biochemical activities,...

Truncated PTH Analogs Identification of the Minimum Sequence Requirements

Truncation of peptide hormones having more than 15 amino acid residues to smaller yet biologically active and potent analogs is very often a challenging task. Most often truncation not only allows researchers the flexibility cf' synthesizing large numbers of analogs with considerable ease, speed, and at less cost, but the truncated analogs also can be studied more systematically to elucidate the regions within the native peptide sequence that are important for binding and bioactivity. SAR...

H2Receptor Antagonists H2recep

Tors and the prototype Hz-receptor antagonist burimamide were identified in a single paper by Black et al. (69). Burimamide was reported to inhibit both HA- and pentagastrin-stimu-lated gastric acid secretion in rats, dogs, cats, and humans. The potency of burimamide at inhibiting gastric acid secretion far exceeded that produced by anticholinergic drugs and was devoid of apparent side effects. Burimam-ide, however, had poor oral bioavailability and was subsequently replaced by metiamide, which...

Hair Growth Disorders

Common baldness, also known as male-pattern baldness, affects approximately 50 of men by age 50 (72), although it can start as early as the teen years. Till the late 1980s, common baldness was viewed as a merely cosmetic condition that has no health implications with the introduction of hair growth agents, the condition was medicalized and redefined as androgenetic alopecia. Androge-netic alopecia affects women as well, but in a different pattern that is usually referred to as female-pattern...

Historical Background and Overview of Prostanoid Synthesis

Prostanoids are metabolites of C20 fatty acids that act as local hormones in both the periphery and central nervous system (CNS). Classically, they are comprised of the prostaglandins and thromboxanes. However, recently, interest has focused on the isoprostanes, which are formed through the direct oxidation of membrane phospholipids and not through the actions of cyclooxygenase (COX) enzymes. Despite this difference in synthesis, current evidence suggests that they act predominantly through...

H2nVVnh2 h2n Vinh2 h2nWnh2 h2nKJnh

Hn2 And H2n

Hiv-1 and hiv-2 replication were 0.8 and 1.6 nm, respectively (338). In an effort to improve the potential for inhibiting HIV-1 replication, bicyclam-AZT conjugates (78) have also been described The binding region for AMD3100 has been defined through single amino acid substitutions in the extracellular loops (ECLs) and TM regions of cxcr4. ecl-2 contains five acidic residues that have been implicated as an important recognition site of the v3 domain in gpl20. As part of the mechanism for viral...

Pharmacological Action of Nicotine

Nicotine binds selectively to the nicotinic receptors that are present in the adrenal medulla, brain, autonomic ganglia, and neuromuscular junctions. It causes the release of several neurotransmitters and hormones such as acetylcholine, norepinephrine, dopamine, serotonin, arginine vasopressin, j3-endorphin, adrenocorticotropic hormone, and cortisol (187). This neuro-regulatory effect of nicotine is dose-dependent and occurs as plasma nicotine level rises when tobacco is smoked. The...

Therapeutic Market

Lateral Cephalogram Measurements For Osa

The therapy for gastric acid-related gastrointestinal disorders has evolved from nonspecific gastro-protective agents to treatments directed at specific sites regulating the secretion of gastric acid. H2-receptor antagonists and PPIs are currently the major therapies used to inhibit the production of gastric acid. The discovery that H. pylori infection was highly correlated with the presence of duodenal ulcer and hypersecretion of gastric acid has introduced an additional therapy that targets...

Sexual Disorders

Chart Drugs For

The recent extraordinary interest in sexual disorders was primarily spurred by the introduction of sildenafil (Viagra),the first effective oral medication for erectile dysfunction. The unparalleled global media hype that followed the launch of Viagra greatly increased the public awareness of erectile dysfunction and of sexual disorders in general. The enormous public response to sildenafil also stirred a debate over the reimbursement of such therapies and of lifestyle drugs in general. Several...

Adverse Reactions and Toxicity

Toxicity of a contrast medium is attributed to its molecular structure, solution property, formulation, and the amount used as a dose. Toxicity may be further classified as chemotoxic-ity, osmotoxicity, and ion toxicity (407, 459). Chemotoxicity is related to a molecular structure that allows binding to proteins, leading to interaction with biomacromolecules such as enzymes, cell membranes, and cell components. Osmotoxicity is attributed to the hyper-osmolality of contrast media, and a marked...

Cxcr4 Discovery

As mentioned earlier, CXCR4 and CCR5 have together been identified as the main corecep-tors for HIV, acting with CD4 to enable viral entry. More specifically, CXCR4 has been described as an essential coreceptor for T-tropic HIV-1- and HIV-2-mediated fusion (305,306). CXCR4 was first cloned by several groups as an orphan receptor named LESTR, HUMSTR, or fusin (307). Later, SDF-la (CXCL12) was identified as the only ligand for this receptor (308,309). These studies have also shown that SDF-la...

Chemokine hfcUzHlUr Signaling

The intracellular signals involved in chemo-taxis are not yet fully understood, and much of the information available today has been deduced from signaling information for other GPCRs. However, significant new data regarding the chemotactic process have accumulated in recent years. Like other seven-trans-membrane receptors, chemokine receptors couple to G-proteins. Many chemokine-in-duced signaling events are inhibited by Borde-tella pertussis toxin PTX , suggesting that chemokine receptors are...

CXCR4 Receptor Structure Rat and

Human CXCR4 chimeras suggest that ECL-2 of CXCR4 is the major determinant of receptor binding to feline immunodeficiency virus (FIV) (316). Mutation of the DRY motif and the C-terminal tail of CXCR4 did not affect the ability of the molecule to support fusion, suggesting that neither signaling by way of G-protein nor receptor internalization was required for fusion mediated by FIV (316). The contribution of the negatively charged residues in the amino terminal of the CXCR4 receptor has also...

IL5 Knockout and Transgenic Mice

Animal models have helped define the significance of IL-5 and the eosinophil in the disease process. IL5 administered to mice results in an increase of eosinophils (458). Experiments with IL-5-deficient and IL-5-transgenic mice confirm a role for this cytokine in controlling eosinophilia (459,460).In IL-5 knockout mice, no eosinophils are produced in response to parasite infection or sensitization with ovalbumin, and there is minimal development of lung inflammation or tissue damage. When IL-5...

The Dsicovery Of Tnfa

TNFa was originally identified because of its antitumor activity. However, later studies have shown that this cytokine plays a major role in autoimmune diseases and is also involved in multiple activities, including metastasis, viral replication, septic shock, inflammation, and fever. Human TNFa is a protein that exists in both soluble (157amino acids) and transmembrane form (233 amino acids). Soluble TNFa is released from the cell membrane through a TNF-converting enzyme and exists as a...

Structure and Mechanism of 5LO It

Ould be noted that most of the original drug effort targeting 5-LO inhibitors was ne in the absence of any detailed structural knowledge of the enzyme. The amino acid sequence of human 5-LO was not described until 1985 (110), when isolation and cloningshowed both it and rat 5-LO to be 78-kDa proteins iwith 93 homology. In its active form 5-LO is embrane bound purification, therefore, modifies its natural behavior. In 1991 recombinant methods allowed the preparation of pure enzyme in milligram...

Inhibitors of 5Lipoxygenase Activating Protein FLAP

Inhibitors Protein Biosynthesis Drugs

FLAP inhibitors are a novel class of compounds that inhibit cellular leukotriene biosynthesis without acting directly on 5-LO. Instead, they bind to the 18-kDa membrane FLAP, thus preventing the activation of 5-LO. Research at Merck Frosst in 1989 (165, 166) led to the initial FLAP inhibitor, MK0886 (14), and consequently to the discovery of FLAP itself. MK0886 was derived from a series of indole-3-alkanoic acids related to indomethacin, which possessed the dual pharmacological properties of...

LTC Synthase

LTC4 synthase is an 18-kDa integral membrane protein that catalyzes the conjugation of reduced glutathione (GSH)with the epoxide LTA4 to form LTC the intracellular parent of the cysteinyl leukotrienes. The purification and characterization of LTC4 synthase has been hindered because of its instability in the semipurified state and the lack of an abundant source of this enzyme. In 1992 Nicholson (199) was able to specifically label this 18-kDa polypeptide in a human monocytic leukemia cell line...

Biochemical Assays Selectivities and Potencies

One cf the challenges associated with evaluating COX-l COX-2 selectivity is trying to define or identify accurate affinities or dissociation constants for compound comparison. Inhibitory concentration data against purified protein obtained from baculovirus or CHO cells transfected with COX-1 or COX-2 have provided a majority of the information with regard to relative potency of individual agents. A complicating factor is that inhibitory activity exhibits a characteristic time-dependent phe-I...

Oxidation of Retinol

In many other cell types, trans-retinol binds to CRBP and this holo-CRBP serves as the substrate for an oxidative reaction in which the primary alcohol is converted into an aldehyde (Fig. 7.7), yielding retinaldehyde (trans-retinal) (18). CRBP plays an extremely important role both in protecting retinol from non-specific oxidative reactions and in the oxidative reaction to retinaldehyde (18).Indeed, CRBP physically interacts with the enzyme(s) responsible for this oxidation reaction, retinol...

Vitamin D Family

Grow Build

Rickets was first reported in the mid-seventeenth century. It could be lethal, but bone deformation was more common. In the United States, rickets continued to be a problem into the 1930s until vitamin D-fortified milk became common. Older adults show bowlegs characteristic of childhood rickets. There were many attempts at giving calcium and or phosphorous supplements. Finally, it was realized that rickets was not found in sunny climates, and populations whose main source of protein was fish...

Chronic Effects of UVR

There are two adaptive responses to the exposure to UV radiation thickening of the stratum corneum and skin tanning (melanogenesis). Stratum corneum thickening is mediated by UVB, whereas skin tanning can be induced by UVB and UVA (225,261). Thickening of the stratum corneum occurs as an adaptive response to prolonged UVB exposure. The stratum corneum proliferates through increased synthesis of keratin by basal keratinocytes. tanning, or delayed pigment darkening,...

Simulating Effects of Drugs through Cenomics

By coupling yeast genetics with microarray analysis, one can identify the transcriptionally regulated processes associated with each gene. This approach has been successfully used in studying the mitogen-activated protein kinase signaling pathway, allowing identification of new associated regulatory circuits 26, 27 . The mutation of a target protein is also a way to block its activity and simulate the inhibition of the target by a drug. In the study of the CDK inhibitors by Gray et al, 24...

Lipoxygenase Polymorphisms Leuko

Trienes mediate airway inflammation and play an integral role in the pathophysiology of asthma. Zileuton (Zyflo) inhibits the enzyme 5-lipoxygen-ase, reducing the formation of leukotrienes and thus improves the symptoms of asthma. A polymorphism exists in the gene encodingthe 5-lipoxy-promoter region. This polymorphism contains three to six tandem repeats of GGGCGG. A recent study examined the impact of the tandem repeat polymorphism in the ALOX5 promoter region with response to an...

Physiology Of Gastric Acid Secretion

Gastric acid secretion is stimulated by food-related signals that stimulate the release of acid from specialized cells within the stomach. This secretory process has been divided into three phases cephalic, gastric, and intestinal, with each phase leading to different amounts of acid being secreted (Table 3.3). Cephalic Phase. The sight, smell, taste, and sensation of swallowing food causes central stimulation of the vagus nerve leading to Ach release from synapses within the fundic and antral...

Current and Future Trends

It is evident from the number of new cases of skin cancer that there is a need for new sunscreens with better protection. However, the cost and time required for introducing new sunscreen agents through an NDA is prohibitive. Therefore, a large portion of the current research in the field focuses on novel drug delivery systems to prolong the duration of the sunscreening effect, enhance the water resistance (substantivity) of the products, enhance their SPF, or decrease their irritation...

CD437 An Atypical Retinoid

CD437, 6- 3-(1 -adamantyl)-4-hy (AHPN see Fig. 7.23), was originally described as a selective, RARy agonist that may be useful in the treatment of retinoid-sensitive dermatological conditions (203, 205). However, more recently, Fontana and colleagues have discovered that this retinoid induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines (224-232) through a mechanism that does not seem to involve any of the known RAR or RXR subtypes (229). CD437 AHPN even induces...

Clinical Use

Most sunscreens currently in use are compounds that have high absorbance or reflectance throughout the entire W B range, part of the UVA range, and in some instances infrared wavelengths. They are divided into two main groups chemical (organic) and physical (particulate) agents. Physical sunscreening is the only way to block radiation across the entire spectrum (UVB, WA, visible, and infrared) (226). However, in practice, combined chemical sunscreens or combinations of...

Nonviral Vectorrelated Cytotoxicity

It is known from the 1980s that bacterial DNA stimulates the formation of cytotoxic IFN-a , 3, and IL-12 when the DNA is taken up by macrophages. It in turn leads to NK cell activation and production of pro-inflammatory cy-IFN-y. This is accompanied by the proliferation of B-cells and therefore the reduction of apoptosis and release of IL-6 and IL-12 (246-249). These pro-inflammatory effects were found to be caused by some im-muno-stimulatory sequences in prokaryotic DNA that contained...

Helicobacter Pylori H Pylori

H. pylori infection occurs in approximately 40 of the population over 40 years 0f age and most patients with peptic ulcer disease are infected with H. pylori. Because ulcers recur in patients who have undergone successful H. pylori, eradication therapy, infection may not always be causative for the disease. Less than 5 of ulcer patients are H. pylori negative and in H. pylori positive patients only 10 of ulcers recur after eradicating the infection. Likely causes of ulcer recurrence are...

Polycation Condensed DNA Entrapped in Cationic Liposome LPDI Formulation

One of the prerequisites for a bio-entity entering the cell and nucleus is to possess a small size. The delivery of DNA was efficient through cationic lipidic formulation-mediated gene delivery, but the nuclear transport from cytoplasm was quiet an inefficient process 146 . Generally, lipoplexes formed by multiple charged cationic lipids made small 20 nm , highly condensed DNA lipidic complex. These complexes were found to be more trans-fecting than the lipoplex formed by mono-cat-ionic lipids...

Historical Perspective

Naturally occurring retinoic acids and synthetic derivatives exert cellular effects by binding to and activating two families of nuclear receptors (NRs), retinoic acid receptors (RARs Fig. 7.16) and retinoid X receptors (RXRs Fig. 7.17). Both classes of retinoid receptors are comprised of three subtypes, a, p, and y, all of which belong to the steroid and thyroid hormone receptor superfamily of li-gand-dependent transcription factors (1). RARa was the first member of either retinoid receptor...

Gene Delivery for Myocardial Diseases

Naked pDNA transfer into myocardium through direct injection or through coronary vasculature usually showed low transfection efficiencies. The results had nevertheless proven valuable in studies aimed at characterizing the role of promoters in cardiac tissue and for examining the influences of naturally occurring mechanical and hormonal stimuli of the myocardium on expression of transferred foreign genes (40). Kitsis et al. (41) have demonstrated that the tissue-specific promoter chimeras...

Vitamin Drug Interactions 60

Two most clinically significant interactions are phosphate with L-dopa or isoniacid. Examine Fig. 8.36 and note that dopa decarboxylase requires PLP. This enzyme is found both centrally and peripherally. The latter includes the intestinal mucosa. The precursor to dopamine, L-dopa is indicated for the treatment of Parkinson's disease. L-Dopa is prescribed because little dopamine crosses the blood-brain barrier relative to its precursor l-dopa. A patient with Parkinson's disease prescribed L-dopa...

Overthecounter Drugs

In the United States, there are two classes of drug products prescription and nonprescription. Nonprescription drugs are often referred to as over-the-counter drugs because they are available for general sale to consumers without a prescription (17). Consumers can purchase OTC drug products off the shelf from a variety of mass distribution outlets such as convenience, grocery, and drug stores, with the exception of Schedule V Controlled Substance and insulin products, which are kept behind the...

K118614g6-vintage

A number of oxygenated products derived from arachidonicacid, frequently termed eico-sanoids, have profound physiological and pathological effects. The history of these reviews indicates the expansion of the awareness of the medical importance of different classes of eicosanoids. Two editions from this series (1,2) contained one chapter listing pros-taglandins as the only eicosanoid target. The last volume broadly discussed both thromboxanes and leukotrienes together, while downplaying...

IL4 Modulators Clinical Data

Ferent approaches have been taken to neutralize IL-4 activity, including soluble IL-4 receptor, antibodies against IL-4, and mutated IL-4, which acts as an antagonist of the receptor. In a mouse model of airway inflammation, soluble IL-4 receptor administered intranasally, before allergen challenge, results in a reduction of eosinophil infiltration, V-CAM expression, and mucus hypersecretion (417). This treatment, however, did not change airway hyperreactivity in response to methacholine. In...

Targeted Gene Delivery by Antibodies Conjugated with Polycations

Polyamines had shown efficient transfection to lung endothelium. An efficient targeted transfection vector to the lungs could be achieved by conjugating a targeting ligand against platelet endothelial cell adhesion mol-ecule-1 (PECAM-1) to polyamines. This li-gand-polyamine complex was targeted efficiently to the pulmonary endothelial cells. A chemical vector was synthesized by covalent conjugation of polyethylenimine (PEI) and anti-PECAM antibody (Ab) (243). The cat-ionic complex was shown to...

Improving Plasmid Dnamediated Gene Transfer By Electroporation

Electroporation is a process of exposing cells to a controlled electric field for the purpose of cellular membrane permeabilization (61).The intense localized electric pulses destabilize the membrane allowing molecules, which otherwise do not gain access inside the cell, to enter cells. A variety of genetic materials were inserted into the cells in vitro by electroporation (62-64). Electrochemotherapy, a cell elec-tropermeabilization approach that facilitates the cellular entry of hydrophilic...

Burger Memorial Edition

The Sixth Edition of Burger's Medicinal Chemistry and Drug Discovery is being designated as a Memorial Edition. Professor Alfred Burger was born in Vienna, Austria on September 6, 1905 and died on December 30, 2000. Dr. Burger received his Ph.D. from the University of Vienna in 1928 and joined the Drug Addiction Laboratory in the Department cf Chemistry at the University of Virginia in 1929. During his early years at UVA, he synthesized fragments of the morphine molecule in an attempt to find...

Smoking Cessation Agents

Although smoking cessation is a lifestyle decision, the ability to quit is usually hindered by nicotine chemical dependence. According to the Surgeon General report on smoking in 2000 (163), Tobacco dependence is in fact best viewed as a chronic disease with remission and relapse. Even though both minimal and intensive interventions increase smoking cessation, most people who quit smoking with the aid of such interventions will eventually relapse. It is estimated that 24.7 of all adults who...

Will Pharrnacogenornics Improve Medical Care

It is still unclear if prospectively genotyping patients for many of the genetic variants described within this chapter improves medial care and whether it is cost effective. Geno-typing patients for the presence of TPMT deficiency to prevent life-threatening hematological toxicity from azathioprine, mercapto-purine, or thioguanine provides an equivocal advantage compared with empirical dosing. However, in other examples, genotyping may not be an advantage over the current best medical care....