Further Examples of Privileged Structural Motifs

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The biphenyltetrazole moiety is an example of a privileged structure which is found in angiotensin I antagonists such as Losartan (4) [50] and Valsartan (5) [51] and in growth hormone (GH) secretagogue agonist MK-0751 (6) [52] (Fig. 25.6).

The diphenyl methane moiety is another structural motif which is active in a variety of biological targets. The rigidity of the template prevents the aromatics from intramolecular hydrophobic interaction in aqueous media (''hydrophobic collapse'') so that the hydrophobic interaction can promote receptor binding instead [47]. On one hand, it is part of the 5-phenyl-1,4-benzodiazepine substructure (see Sect. 25.5.1); on the other, it is, for example, part of the NPY Y1 antagonist (7) BIBP 3226 [48], of angiotensin AT-2 ligand (8) PD 132 177 [26], and of neurokinin NK1 antagonist quinuclidine (9) CP 96345 [53] (Fig. 25.7).

As shown in Fig. 25.8, arylspiropiperidines also display a broad range of activities. Examples include the chemotaxin C5a receptor agonist 10 [54], the oxytocin antagonist 11 [55], and the growth hormone secretagogue 12 [52] (Fig. 25.8).

A more general description of central nervous system (CNS) drugs shows that many of them descend from a simple aromatic system and an amine which is fixed via a two- to five-atom chain to the hydrophobic core [56]. For example, the dopamine antagonist chlorpromazine (10) and the 5-hydroxytryptamine (5-HT)

Fig. 25.7. Diphenylmethanes as privileged substructures.

Fig. 25.7. Diphenylmethanes as privileged substructures.

Fig. 25.8. Arylspiropiperidines as privileged substructures.

Fig. 25.8. Arylspiropiperidines as privileged substructures.

Fig. 25.9. Arylalkylamines as CNS drugs.

Fig. 25.9. Arylalkylamines as CNS drugs.

uptake inhibitor imipramine (11) contain this substructure, as do the anticonvulsant drug procyclidine (12) and the heroin substitute analgesic methadone (13)

This principle is not only limited to CNS drugs. The calcium antagonist verapamil (14), the b-blocker propanolol (15) and tamoxifen (16), an antiestrogen, share the same substructural unit [57] (Fig. 25.10).

The 2,2-dimethylbenzopyran substructure is a common subunit in natural products as well as in pharmaceutically active substances. Nicolaou et al. presented a solid-phase synthesis of a series of libraries based on this scaffold (Scheme 25.1) [58-60]. They used a selenium-based linker which proved to be stable over a range of reaction conditions (e.g. reductions, Li-organyls, Stille coupling conditions, condensation reactions, hydrazines), but was selectively cleaved with hydrogen peroxide, thus yielding the benzopyran in kind of a traceless linker system.

Fig. 25.10. Arylalkylamines which are not CNS drugs.

Fig. 25.10. Arylalkylamines which are not CNS drugs.

Scheme 25.1. Synthesis of dimethylbenzopyrans on solid phase. 25.5.3

Substructure Analysis of Drugs

Scheme 25.1. Synthesis of dimethylbenzopyrans on solid phase. 25.5.3

Substructure Analysis of Drugs

In a paper by Bemis and Murcko [61], a database of 5120 known drugs [Comprehensive Medicinal Chemistry (CMC)] was analyzed for the molecular frameworks of the drugs. These authors defined the framework of a drug as the union of all ring systems and linker atoms on the direct path between the ring systems. On the basis of the two-dimensional representations of the drugs (ignoring atom type, hybridization, and bond order), they found 1179 different frameworks, but only 32 of these accounted for half of all frameworks. A few representative samples of these are outlined in Fig. 25.11. The numbers show the frequency of each framework within the database.

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