I

Figure 1.16. Synthesis of benzodiazepine libraries —3.

Similar to Rgure 1.16

arm-

Similar to Rgure 1.16

arm-

Figure 1.17. Synthesis of benzodiazepine libraries-4.

Figure 1.17. Synthesis of benzodiazepine libraries-4.

vincing proof that combinatorial chemical methods would be of dramatic use in prepar-ingagents likely to become orally active drugs.

Benzodiazepine libraries (123) and close analogs such as l^-benzodiazepin^ö-diones (124, 125) continue to be popular. For example, one such library is prepared by a sequence involving a Borch reduction and an internal ester-amide exchange to form the seven-mem-bered ring and then cleavage from the resin. The reaction conditions are mild enough to preserve the optical activity in this library (Fig. 1.19) (126). Use of peptoid starting materials and reductive traceless linker technology are features of the work of Zuckermann et al. (Fig. 1.20) (125).

Representative of another important class of drugs is the 1, 4-dihy dropyridines. Hantzsch methodology (without the oxidative step) works efficiently on resins for this purpose. The conditions are mild in this synthesis and the yields are good (Fig. 1.21) (127).

Angiotensin-converting enzyme inhibitors are million dollar molecules. An interesting library of captopril analogs were prepared on resin using a split-mix iterative resynthesis deconvolution procedure. From a collection of about 500 analogs, an analog emerged that was threefold more potent than captopril itself and possessed a K{ of 160 pM (Fig. 1.22) (128)!

Another important class of contemporary drugs that have been made in library form, in this case both in solution and in solid state, are the fluoroquinolone antimicrobial agents (Fig. 1.23) (129, 130). The solution-based yields were superior to those obtained on the resins.

Synthesis Benzodiazepine Library
Figure 1.18. Synthesis of benzodiazepine libraries—5.

i. Borch reductive alkylation with aminoacid ester ii. Anthranilic acid amidation

Figure 1.19. Synthesis ofbenzodiazepine libraries—6.

R1. /C02Me i. BrCH2C02H

ii. Amino acid ester

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