Structure-Based Design and Synthesis of Substituted 2-Butanols as Nonpeptidic Inhibitors of HIV Protease:  Secondary Amide Series

Abstract

The design, synthesis, and crystallographic analysis of protein-inhibitor complexes is described for a novel series of nonpeptidic HIV protease (HIV Pr)inhibitors. Beginning with a cocrystal structure of a Phe-Pro peptidomimetic bound to the HIV Pr, design was initiated that resulted in the substituted 2-butanol compound 8 as the lead compound (Ki = 24.5 microM, racemic mixture). Modifications on the initial compound were then made on the basis of its cocrystal structure with HIV Pr and inhibition data, resulting in compounds with enhanced potency against the enzyme (compound 18, Ki = 0.48 microM). These inhibitors were found to bind to the enzyme essentially as predicted on the basis of the original design hypothesis. Stereospecific synthesis of individual enantiomers confirmed the prediction of a binding preference for the S alcohol stereochemistry. Modest antiviral activity was demonstrated for several of the more potent HIV Pr inhibitors in a HIV-1 infected CEM-SS cell line.

Design, Synthesis, and Biological Evaluation of Novel C14−C3′BzN-Linked Macrocyclic Taxoids

“…As Scheme 2 shows, (3 R ,4 S )-β-lactams 3a-d were prepared in excellent yields through the acylation of enantiopure β-lactams 1a , b with the corresponding 2-alkenylbenzoyl chlorides 2a-c 34-36 in the presence of triethylamine and DMAP.7-TES-14β-allyloxy-baccatin 6 was prepared, following the method previously reported by us from 14-OH-DAB through selective acetylation of the C10-hydroxyl group37 and subsequent TES protection of the C7-hydroxyl group (83% for two steps, Scheme 3). 8 The Ojima-Holton coupling of β-lactams 3a-d with baccatin 6 was carried out under the standard conditions (LiHMDS in THF at −30 °C) to give the corresponding paclitaxel-dienes 7a-d bearing olefinic groups at the C14 position as well as the ortho position of the C3’BzN moiety (Scheme 3).…”

INHIBITORS OF HIV-1 PROTEASE: A Major Success of Structure-Assisted Drug Design

“…Studies examining the physicochemical properties of the former utilized the unpublished crystal structure of this inhibitor complexed with HIV-1 PR for testing of conformationally flexible docking by evolutionary programming (36,69). This work was followed by further developments in the design strategy of nonpeptidic inhibitors (73,90). Nelfinavir was rapidly approved by the FDA (under the name Viracept) and was the first of the protease inhibitors to be approved for the treatment of pediatric AIDS.…”

One‐Pot Sequential Schmidt and Ritter Reactions for the Synthesis of N‐tert‐Butyl Amides

“…Similarly, saquinavir, the first HIV protease inhibitor, is currently undergoing clinical evaluation and contains the N ‐ tert ‐butyl amide moiety 3. Moreover, Agouron Pharmaceuticals has recently synthesized some diarylbutanols4,5 that also bear the N ‐ tert ‐butyl amide moiety. These molecules are known to exhibit potent anti‐HIV protease activities as well.…”