John J Wright

Active site-directed thrombin inhibitors--II. Studies related to arginine/guanidine bioisosteres.

A series of N-arylsulfonylarginine amides was synthesized wherein the guanidine or arginine moiety was isosterically replaced by a number of heterocyclic functionalities. These compounds were evaluated as potential active-site inhibitors of thrombin. Bisamidines 11a-n showed a similar SAR to that of simple arginine compounds. The ex vivo clotting time measurement of 11d after ip dosing showed prolongation of clotting time in rats.

Novel mimics of sialyl Lewis X: design, synthesis and biological activity of a series of 2- and 3-malonate substituted galactoconjugates.

A series of potent inhibitors of P-selectin as potential anti-inflammatory agents is reported. These compounds are derivatives of galactocerebrosides bearing a malonate side chain in positions 2 and 3 of the galactose moiety. Based on the binding mode of sialyl Lewis X, the two acidic groups of the malonate are designed to form ionic interactions with two important lysines in the active site of P-selectin, Lys113 and Lys111. On the other hand, the 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the calcium ion in the P-selectin active site. The synthesis and the biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.

HMG-CoA reductase inhibitors 4. Tetrazole series: conformational constraints and structural requirements at the hydrophobic domain.

Abstract Synthesis analogs 2–5 were prepared and the inhibitory activity was evaluated in order to assess the conformational constraints and the minimal structural requirements associated with the hydrophobic terminus of these tetrazole-derived dihydroxy acids for optimum potency.

Enzyme inhibitors of the renin-angiotensin system.

The primary purpose of this review is to summarize new developments in the area of inhibitors of the renin-angiotensin system. Specifically, inhibitors of the two main enzymes involved in the generation of angiotensin II, renin and angiotensin-converting enzyme (ACE), will be examined. This review will concentrate primarily on novelty, either chemical or pharmacological, rather than cataloging anticipated and similar results of closely related analogs.

Synthesis of tetrazol-1-yl analogs of HMG-COA reductase inhibitor BMS180431 (formerly BMY21950)

Abstract A series of tetrazol-1-yl analogs were prepared and compared with the corresponding parent tetrazol-5-yl HMGCO-A reductase inhibitors. The generally weaker enzyme inhibitory activity of 2a may be attributed to the shorter distance between the heterocycle and the backbone of the molecule. The corresponding unsubstituted tetrazole parent compound (2c) becomes the most active in this series.

3-Hydroxy-3-methylglutaryl-coenzyme a reductase: Three-dimensional structure-activity relationships and inhibitor design

The inhibition of HMG-CoA reductase is an efficient way to lower plasma chlosterol levels in humans. The 9,9-bis (4-fluorophenyl)-3,5-dihydroxy-8-(substituted)-6,8-nonadienoic acids analogues represent a novel class of HMG-CoA reductase inhibitors developed at Bristol-Myers. The goal of this study was to delineate from inhibitory potency values the main topographical and physico-chemical features of the binding site probed by the substituent attached to the C8 position of the analogues. Using a combination of receptor mapping and 3D-QSAR it was possible to obtain a quantitative map of the binding site which relates the HMG-CoA reductase inhibitory potency to the shape and size of both the binding site and C8-substituent of the inhibitor. We prove that the 3D-QSAR derived here is reliable, robust, and affords predictive utility.