Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors.

Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 6 has exhibited exceedingly potent inhibitory activity against memapsin 2 and selectivity over memapsin 1 (>3800-fold) and cathepsin D (>2500-fold). A protein-ligand crystal structure revealed cooperative interactions in the S2- and S3-active sites of memapsin 2. These interactions may serve as an important guide to design selectivity over memapsin 1 and cathepsin D.

Structure-based design: synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors.

The structure-based design and synthesis of a series of novel nonpeptide HIV protease inhibitors are described. The inhibitors were designed based upon the X-ray crystal structure of inhibitor 1 (UIC-94017)-bound HIV-1 protease. The inhibitors incorporated 3-hydroxysalicyclic acid-derived acyclic and cyclic P2 ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. The inhibitors contain only two chiral centers and are readily synthesized in optically active form utilizing Sharpless asymmetric epoxidation, regioselective epoxide opening, and ring-closing olefin metathesis using Grubbs' catalyst as the key steps. We have synthesized 13-15-membered cycloamides and evaluated their HIV-1 protease enzyme inhibitory and antiviral activities in MT-2 cells. Interestingly, all cycloamide-derived inhibitors are noticeably more potent than the corresponding acyclic compounds. The ring size and substituent effects were investigated. It turned out that the 14-membered saturated ring is preferred by the S(1)-S(2) active sites of HIV-1 protease. Macrocycle 26 showed excellent enzyme inhibitory potency with a K(i) value of 0.7 nM and an antiviral IC(50) value of 0.3 microM. In view of their structural simplicity and preliminary interesting results, further optimization of these inhibitors is underway.

Novel cyclourethane-derived HIV protease inhibitors: a ring-closing olefin metathesis based strategy.

A series of novel macrocyclic urethanes incorporating a (R)-hydroxyethylamine isostere was designed and synthesized. Ring size and substituent efffects have been investigated. Cyclourethanes containing 14- to 16-membered rings exhibited low nanomolar inhibitory potencies against HIV-1 protease.

Antiviral activity of UIC-PI, a novel inhibitor of the human immunodeficiency virus type 1 protease.

The human immunodeficiency virus type 1 (HIV-1) protease inhibitor UIC-PI (1) was developed via structure-based design and incorporated a novel bis-tetrahydrofuran (bis-THF) ligand in the (R)-(hydroxyethyl)sulfonamide based isostere. The EC(50) and EC(90) of the compound in acutely-infected H9 cells were <1 and approximately 1 nM, respectively. In chronically infected H9/HIV-1(IIIB) cells, the EC(50) and EC(90) were 20 and 50 nM, respectively. In parallel studies comparing UIC-PI and saquinavir in H9/HIV-1(IIIB) cells, viral p24 levels in culture supernatants were an order of magnitude lower with UIC-PI than with saquinavir.

Convenient synthesis of novel macrocyclic urethanes: alkoxycarbonylation of amines and ring-closing metathesis strategy.

Alkoxycarbonylation of amines followed by ring-closing metathesis of the resulting dienes with Grubbs catalyst (25-50 mol%) provided convenient access to 14-16 membered macrocyclic urethanes in very good yields. 0 1998 Elsevier Science Ltd. All rights reserved.

ESTER DERIVED TITANIUM ENOLATE ALDOL REACTION: HIGHLY DIASTEREOSELECTIVE SYNTHESIS OF SYN- AND ANTI-ALDOLS.

Aldol reactions of bidentate aldehydes and cis-1-arylsulfonamido-2-indanyl ester derived titanium enolates proceed with excellent syn-diastereoselectivities and good to excellent isolated yields.