Il4

Th2-type cytokines such as IL-4, IL-5, and IL-13 orchestrate a cascade of events during development of an allergic inflammatory response. This is demonstrated both clinically and in preclinical animal models (404, 405). IL-4 plays a critical role in the early commitment of ThO cells to Th2 cells and regulates IgE secretion by B-cells. It also induces V-CAM expression on endothelial cells, promotes eosinophilic inflammation, and increases airway mucus production. In asthmatic patients there is...

Peptide Leukotriene Antagonists

There have been thousands of compounds prepared as CysLT antagonists, of which perhaps two dozen have made it to Phase I safety studies in humans. In this section, we focus on a few key compounds, especially those that have advanced to clinical studies. For more detail, the reader is referred to several excellent reviews by Shaw (203), Salmon (204), and Brooks (205). Testing for leukotriene antagonism as for LT inhibition has required many biochemical, pharmacological, and...

CCR2 Small Molecule Antagonists

The in vivo efficacy seen with anti-MCP-1 antibodies and peptide antagonists prompts the search for small molecule CCR2 antagonists. The spiropiperidines (18-20) are early examples of CCR2 antagonists, as determined by 125I-MCP-1 binding and chemotaxisin THP-1 cells (110).As noted above with the CCR1 antagonists, a basic nitrogen is a common feature within this class of antagonists. Site-di-mutagenesis suggests that this nitrogen may form a critical recognition with an anionic residue (E291) in...

Polymorphisms in Drug Target Genes and Clinical Efficacy

The biomedical literature contains a multitude of publications that attempt to correlate genetic variation underlying differential response to medications. It is obviously not feasible to review all of the examples from the literature, however, Table 12.5 summarizes several of these polymorphisms that are associated with altered drug response. Our goal is to provide several illustrative examples of how polymorphisms in drug targets are being used to establish a personalized medicine platform....

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...

Peptide Leukotriene Antagonists of Diversified 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...

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

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...

References

Feldman, Cytokine Reference, Vol. 1, Academic Press, London, 2001. 2. K. i. Arai, F. Lee, A. Miyajima, S. Miyatake, N. Arai, and T. Yokota, Annu. Rev. Biochem., 59, 783 (1990). 3. T. A. Springer, Cell, 76,301 (1994). 4. C. R. Mackay,Nat Immunol., 2, 95 (2001). 5. A. Zlotnik, J. Morales, and J. A. Hedrick, Crit. Rev. Immunol., 19,1 (1999). 6. A. Mantovani, Immunol. Today, 20, 254 7. M. Baggiolini, Nature, 392, 565 (1998). 8. A. Zlotnik and 0. Yoshie, Immunity, 12, 121 9. A....

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,...

Retinoid Metabolism

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)....

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...

Ch2oh

Male and 1.2 g I kg for female mice, corre-spondingto a particle mass of 3.1 and 2.6 g kg body weight, respectively. Liver attenuation enhancement was 38 HU after intravenous injection of 200 mg I kg of the carbonate particles in normal rabbits and rabbits with implanted VX2 carcinoma. Attenuation enhancement was dose dependent and increased with the dose. At a dose of 270 mg I kg the attenuation enhancement was 110 HU. Liver enhancement reached maximum approximately 30 min after injection, and...

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...

Choh Iohexol choh

Smiles rearrangement, an intramolcular nu-cleophilic aromatic substitution, in which the substituent 5- (hydroxyacetyl)methylamino group is rearranged to form the 5- methylami-nocarbonylmethoxy group. This reaction uncouples and replaces the N C bond with the bond between the substituent and the ring intramolecularly (253). The rearrangement is reversible, with sodium hydroxide or sodium methoxide catalyzing the forward reaction. Ioversol, iopamidol, and a dimer also undergo the Smiles...

Test Assays For Studying i Gastric Acid Inhibitors

Gastric acid secretion occurs through receptor-mediated or enzyme-mediated processes. Drug dissociation constants can be determined from in vitro bioassays, allowing affinity estimate comparisons to be made between compounds. Functional evaluation can be made using both in vitro and in vivo techniques, with the latter models being able to provide information on the pharmacokinetics of drug candidates. Technological progress made since the discovery of both H2-receptor antagonists and PPIs means...

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...

Intravenous Injection

This is a widely used mode of gene delivery in animals. On injecting liposome DNA complex (lipoplex) intravenously (IV), Stewart et al. for the first time showed the residence of DNA primarily in heart and lungs even after 9 days with minimal toxicity. IV-injected lipo-plex expressed transgene in almost all organs, includingthe lung, kidney, heart, spleen, liver, brain, etc., and the expression stayed for 9 weeks with apparently no treatment-related toxicity (176). Toxicity and antitumor...

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...

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,...

PK2

168-169 Insol. 5-5.5 261,286 acid acid acid acid acid N,N'-Bis-(2,3-dihydroxypropyl)-5- JV' -dimethyl-1,3-benzene-dicarboxamide 5- Acetyl(2,3-dihy droxypro-py 1) amino -N,N' -bis- -2,4,6-triiodo-1,3-benzenedicarboxamide (S)-N,N' Melting ,D50) g kg Solubility, g Point or I ( g 100 mL H20 CO__I kg)_at 20 C pK& h2q25 Ref. 174-180 12.1 g I kg Sol. 193,302 > 300 (dec) 11.3 g I kg Very sol. OS)- 10.79 196,302, 5- ( )-JV,AT-Bis(2,3-dihydroxy-pro-pyl) -2,4,6-triiodo-JV-methyl-...

Inhibitors of 5Lipoxygenase 5LO

The mechanism of 5-LO appears to involve the oxidized active Fe3+ state and the generation of radical species (2). Known mechanisms of , inhibition constitute trapping of radical intermediates, ferric iron ligation, reduction of the nheme iron, reversible binding at active or other regulatory sites, and combinations of these effects in the same molecule. Consequently, three broad classes of direct 5-LO inhibitors have evolved over the last 15 years redox, iron ligand, and nonredox inhibi-First,...

OTC Drug Review In the 1960s the

OTC drug market back then was similar to today's market in that there was a proliferation of products based on the same actives (24-28). For this reason, it became impossible to review every OTC product on the market. For practical reasons, the FDA decided to review active ingredients by therapeutic categories instead of individual finished products. In 1972, the FDA initiated the OTC Drug Review process. The goal of the OTC Drug Review was to determine which active ingredients and their...

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...

Introduction

Vitamins are enjoying renewed popularity with the lay public that, in some ways, mimics the attention seen in the early part of the twentieth century when they were first being discovered. Paralleling the interest by the general public is increased focus on the biochemical role of vitamins at the molecular level. Some vitamins can be considered prototypes for pharmacological agents used to treat diseases that do not appear directly related to the patient's vitamin status. Although all animals...

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...

Dietary Reference Intakes DRIs 3

The adult DRI values for each vitamin are und in the section for that vitamin. 2.3.1 Introduction. The last official set of ference values were the 1989 Recommended ietary Allowances (RDAs) for the United States and 1990 Recommended Nutrient In takes for Canada. These are being replaced by the Dietary Reference Intakes, a joint effort of the United States and Canada. The DRIs are published by the Food and Nutrition Board of the National Academy of Sciences National Research Council. The expert...

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...

O2c nh3

Biosynthesis of NAD from tryptophan. namide, but not tryptophan and niacin equivalents (see next section). Large doses of niacin and niacinamide do have adverse reactions. These are sometimes seen with patients who are prescribed niacin in doses up to 2 g daily for hyperlipidemia, including both hypercholesterolemia and hypertriglyceridemia. For the former, there is the desired decreased LDL and increased HDL. Adverse reactions include vasodilation from niacin, particularly in the...

Clinical Relevance

Historically, pharmacogenetics targeted its pursuit on the reasons for toxicity and therefore drug safety. However, it is pharmaco- genomics that promises to deliver individualized pharmacotherapy with greater efficacy (5) while still limiting toxicity. An example of the potential for improved efficacy is given in the example of clozapine. Clozapine is an atypical antipsychotic with superior efficacy in patients with treatment resistant schizophrenia. Despite being an effective anti-psychotic,...

What Do The Pills Saviprazole Treat

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...

History

The use of drugs for the treatment of impotence and other sexual disorders is very old. Yohimbine has been used in folk medicine by men and women for various forms of sexual dysfunction, mainly as an aphrodisiac for over a century. In the United States, yohimbine hy-drochloride has been marketed and prescribed by doctors for more than 75 years (154). Be cause the mainstream medical use of yohimbine pre-dated the Food and Drug Act, the drug did not go through the formal FDA review and approval...

LTB Antagonists Related to HAPType LTD4 Antagonists

A team at Eli Lilly discovered that moving the alkyl chain from the hydroxyacetophenone (HAP) 3-position, as found in FPL-55712 (28), resulted in selective LTB, antagonists. For example, LY255283 (41) inhibited LTB4 binding to neutrophils with an IC value of 87 nM (264). Further work in this class yielded LY293111 (42), which was active in blocking LTB4-induced bronchoconstriction in vivo (265). A publication on LY293111 has appeared describing its pharmacology in vivo (266). Unfortunately, the...

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...

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...

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...

IL13 Knockout and Transgenic Mice

The role of IL-13 in vivo has been studied by use of transient or constitutive expression of the cytokine. When IL-13 was expressed in an inducible fashion in the lung, a very striking phenotype was observed (552) mucus metaplasia, macrophage, lymphocyte, and eosino-phil-rich inflammation and subepithelial fibrosis are characteristics shown by these mice. These same features can also be found in asthmatic patients. These experiments suggest a role for IL-13, not only in the allergic response...

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...

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...

Ccr4

CCR4 was originally cloned by Power and colleagues from a basophilic cell line (163). RNA for CCR4 is expressed in stimulated T-cells, B-cells, monocytes, platelets, and, to a lesser extent, in basophils (163,164). CCR4 has been linked to Th2 cell polarization (165-167) and the expression of CCR4 was strongly upregu- lated upon activation through the T-cell receptor or by other cytokines such as transforming growth factor j3 (TGF-J3) (166,167). Two high affinity ligands have been described for...

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...

Chemistry and Structure Activity Relationships

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....

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...

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...

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...

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,...

Structure Activity Relationships

Melanotropins, a-, jS-, and y-melanocyte stim ulating hormone (MSH) are a group of endogenous neuropeptides that control various key physiological functions through their interaction with the five transmembrane G-protein-coupled receptors (GPCRs), called the melano-cortin receptors (MCRs). To date, five such receptors (123-129) have been identified the MC1-R a-MSH receptor (pigmentation receptor) the MC2-R ACTH receptor recent research has revealed that the MC2-R binds ACTH with high affinity,...

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...

C T Peng

Department of Pharmaceutical Chemistry San Jose State University Nuclear Science Facility Jose. California 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 2003John Wiley & Sons, Inc. 3 Classification of Radiopaques, 486 4 Heavy Metals and Their Salts, 486 4.2.5 Ultrasmall Ferrites, Gd-Chelates, and MRI, 490 4.2.8 Other Metallic Salts, 493 6 Organic Iodine Compounds, 495...

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...

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...

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...

H2n s

Marketed H2-receptor antagonists. Figure 3.4. Marketed H2-receptor antagonists. such as acidity, hydrophilicity, dipole moment, conformation, and geometry of the hydrogen-bonding group (80), that it was possible to retain H2-receptor antagonism in a variety of structures. For example, it was possible to replace the thiourea and cyanoguani-dine groups of metiamide (81) and cimetidine (82) with nitroguanidine and diaminonitro-ethylene, respectively, which in this instance proved to be...

H3c n

Pyridoxal phosphate-isoniazid interaction. research done on this vitamin and, therefore, it has adequate intakes (AI) and no RDAs. 3.9.1 Chemistry, Uptake, and Metabolic Role. This vitamin, which can be considered a derivative of j3-alanine, is asymmetric (Fig. 8.38). The natural form has the B(+) configuration. The L( ) stereoisomer is inactive. The reduced alcohol form, pantothenol, is considered as equally active as the parent acid. Many of the multiple vitamin products use a...

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...

Ai Drug Discovery

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...

Structural Features of COX1 and COX2 Enzymes

A large body of structural biology information on the two cyclooxygenases, COX-1 and COX-2 (PGHS-1 and PGHS-2) now exists. Overall, the data indicate a remarkable degree of similarity between the enzymes. They differ in length by only 11 amino acids, with COX-2 being slightly larger. The differences in sequence are predominantly in the membrane-binding domain. The overall structure of the human and mouse COX-2 is superimposable on the ovine COX-1 structure (280). Both enzymes are dimers with...

Preface

The Editors, Editorial Board Members, and John Wiley and Sons have worked for three and a half years to update the fifth edition of Burger's Medicinal Chemistry and Drug Discovery. The sixth edition has several new and unique features. For the first time, there will be an online version of this major reference work. The online version will permit updating and easy access. For the first time, all volumes are structured entirely according to content and published simultaneously. Our intention was...

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...

Concluding Remarks

DNA microarray technology is proving to be a powerful genomics-based tool in a broad range of biomedical fields. In the field of drug development, this technology can provide insight into the full complement of cellular targets with which a drug might interact and assist in defining mechanisms of action. In the context of patient treatment, gene expression profiles can provide information that will assist in predicting the cellular response to a drug. Further, gene expression profiling is on...

CCR5 Small Molecule Antagonists

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...

Physiology and Pharmacology

UV radiation has both acute and delayed adverse effects on the human skin. The acute effects are inflammation and sunburn, and the delayed or chronic effects are primarily photo-aging and photocarcinogenesis. The susceptibility of individuals to the harmful effects of UV radiation depends on several factors (1)skin pigmentation, (2)ype and amount of radiation, (3) skin hydration, (4) thickness of the stratum corneum and epidermis, and (5) the distribution and concentration of peripheral blood...

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...

Inhibitors of 5Lipoxygenase Activating Protein FLAP

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...

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...

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...

In Vivo Activities and Clinical Studies with NHydroxyurea Inhibitors BWB70C

Is efficacious in allergen-induced bronchocon-striction and late-phase lung eosinophil accumulation in sensitized guinea pigs (133). Unfortunately, it produced kidney lesions in the rat, preventing clinical evaluation. Zileuton however, was approved for use in the treatment of moderate to severe asthma in 1996 as Zyflo. Several summaries of the clinical studies on Zyflo have since been published (134, 135). Thus we will summarize only the pertinent development events and key clinical findings....

Ln s Ab c

Roentgenography of gastrointestinal tract where X N(Ac) or CO(NCH3) B (CH2CHCH20)2(CH2)4(0CH2CHCH2)2-, 3. Mixtures of iodobenzoic acid derivatives and cellulose derivatives Z H, halo, Ci-C2o alkyl, cycloalkyl, lower alkoxy, cyano R C2-C25 alkyl, cycloalkyl or halo-lower alkyl, fluoro-lower alkyl, aryl, lower alkoxy, hydroxy, carboxy, lower-alkyl carbonyl or lower alkoxy-carbonyloxy or (CR1R2)p-(CR3 CR4)m Q or (CR V C C-Q Rlf R2, R, R4 lower alkyl or halo-alkyl X 1 3 y 1-4 n 1-5 m 1-15 l-15 p...

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 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...

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 >...

Therapeutic Market

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...

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...

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...

Sunscreens

Most people are at least occasionally exposed to the sun for extended periods of time, either as a result of their lifestyle and recreational activities or as a normal part of their jobs. The main adverse effects to exposure to the sun-' light are sunburn, photoaging, and skin cancer. Skin cancer is the most common type of cancer, accounting for almost 40 of all malignancies (221).According to the American Cancer Society, overl.3 million people will be diagnosed with nonmelanoma skin cancer in...

Reversible Proton Pump Inhibitors

The effectiveness of clinically available PPIs relies on the number of active pumps at any one time and the recovery of pumps after biosynthesis. The prolonged suppression of gastric acid secretion produced by both H2-recep-tor antagonists and PPIs produces extended periods of hypergastrinemia, which has been associated with the formation of precancerous changes in human gastric mucosa and gastric in long-term animal studies. In fact, the development of omeprazole, a protonpump inhibitor, was...

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...

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...

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...

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...

Insulin and Hypoglycemic Agents

Repaglinide Nateglinide

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,...

Info

Two key aromatic substituents on the scaffold, is currently not well developed. Although x-ray structures and modeling techniques have provided valuable gross features of the enzyme, to date a large number of X-ray structures with bound ligands have not been available. The scaffold model does seem valid, based on the wide range of heterocycles that have been used and, with a few exceptions see 65a and the other non-l,3-carbonyl analogs 66a and 67b , most produce potent COX-2 inhibitors with...

Lifestyle and Overthe Counter Drugs

Khawla Abu-Izza Sanofi-Synthelabo Research Malvern, Pennsylvania Wyeth Consumer Healthcare Richmond, Virginia Wyeth Consumer Healthcare Hampshire, United Kingdom 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 gt 2003John Wiley amp Sons, Inc. Burger's Medicinal Chemistry and Drug Discovery Sixth Edition, Volume 4 Autocoids, Diagnostics, and Drugs from New Biology Edited by...

Contents

1 INSULIN AND HYPOGLYCEMIC AGENTS, 1 Mark Sleevi Insmed Incorporated Richmond, Virginia 2 PEPTIDE AND PROTEIN HORMONES, PEPTIDE NEUROTRANSMITTERS, AND THERAPEUTIC AGENTS, 45 Victor J. Hruby Catherine Gehrig de Chavez Malcolm Kavarana University of Arizona Department of Chemistry Tucson, Arizona 3 INHIBITORS OF GASTRIC ACID SECRETION, 85 James Black Foundation London, United Kingdom 4 CHEMOKINE AND CYTOKINE MODULATORS, 129 Maria Elena Fuentes Tara Mirzadegan Robert S. Wilhelm 5 COX-2 INHIBITORS...

Ch2co2h

R1 mono- or polyhydroxyalkyl R2 H, alkyl, R1 R3 mono- or dihydroxyalkyl Z bond, alkylene optionally with O interrupters or OH or alkoxy substituents. R1 H, alkyl, R2 R4 poly hydroxyalkyl R3 alkyl, R4 R5 H, alkyl, poly hydroxy alkyl X HO- or alkoxy-substitutedXO-interrupted C alkylene. I R1 H, lower alkyl, R2 R2 straight or branched mono- or polyhydroxyalkyl R3, R4 H, lower alkyl n 1, 2. II R, R1 same or different, a straight or branched mono- or poly-hydroqalkyl C -Cg residue containing 1 to 2...

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...

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...

Alprostadil Prostaglandin E Alpro

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...

Receptor and Receptor Subtype Selective Retinoids

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...

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....

TNFa Knockout and Transgenic Mice

The role of TNFa in vivo is not well understood. It is believed that TNF is required for protection against bacterial, fungal, parasitic, and perhaps even viral infections and other stressful stimuli 562 . TNF knockout mice are shown to develop normally. These mice have normal thymus, but their spleen architecture is abnormal and their ability to fight infection is reduced 563 . They are also protected from lethal doses of LPS. Knockout studies of the TNF receptor p60 have shown that mice...

Selective NSAIDs and NSAIDs Modified for Improved COX2 Selectivity

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...

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...

CCRl Small Molecule Antagonists RP23618 1is an early example of a nonpep

Tide small molecule chemokine antagonist 84 . This compound inhibits 125I-RANTES binding to THP-1 cell membranes IC50 3 fjM . The chemokine receptors CCRl and CCR2 have been detected by RT-PCR as being present on this cell type 62 . However, because 1 inhibits RANTES-induced chemotaxis and has no effect on an MCP-l-stimu-lated chemotactic response, this compound appears to be CCRl selective. Because 1 is not competitive with RANTES, it is presumed to bind at an allosteric site. There is a...

Polycation Condensed DNA in Anionic Liposomes Lpdii Formulation

Some disadvantages always accompany the cationic lipid-mediated gene transfection. Cytotoxic effect in cells tissues is the primary concern, which requires early attention. The cationic lipids exhibit relatively large sizes, whereas complexation with DNA provide suboptimal DNA condensation and have limited efficiency and lack of tissue specificity. Anionic liposomes used in gene therapy have shown poor encapsulation efficiencies because of large size and excessive negative charge of uncondensed...