Chongqing Sun

Dual metalloprotease inhibitors. I. constrained peptidomimetics of mercaptoacyl dipeptides

Abstract A series of benzo-fused lactams were incorporated as conformationally restricted dipeptide mimetics of Ala-Pro in dual-acting ACE/NEP inhibitors 1 and 2. The result of this modification led to compounds possessing excellent inhibitory potency versus ACE and NEP both in vitro and in vivo.

Dual metalloprotease inhibitors. II. Effect of substitution and stereochemistry on benzazepinone based mercaptoacetyls

Abstract A structure-activity study of dual-acting ACE/NEP inhibitor 1A was initiated in order to ascertain what parameters effect in vitro activity versus ACE and NEP. Unlike NEP, ACE was found to be remarkably tolerant to a wide variety of permutations with respect to both the lactam nucleus and the pharmacophore side chain.

The Guinea Pig as a Preclinical Model for Demonstrating the Efficacy and Safety of Statins

Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526 [{(3R,5S)-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced myotoxicity at doses near the ED50 for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model, which used statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.

Microsomal triglyceride transfer protein inhibitors: discovery and synthesis of alkyl phosphonates as potent MTP inhibitors and cholesterol lowering agents

A series of newly synthesized phosphonate esters were evaluated for their effects on microsomal triglyceride transfer protein activity (MTP). The most potent compounds were evaluated for their ability to inhibit lipoprotein secretion in HepG2 cells and to affect VLDL secretion in rats. These inhibitors were also found to lower serum cholesterol levels in a hamster model upon oral dosing.

Dual metalloprotease inhibitors. IV. Utilization of thiazepines and thiazines as constrained peptidomimetic surrogates in mercaptoacyl dipeptides

Abstract A structure-activity study of the dual acting ACE/NEP inhibitors related to 1a and 1b was undertaken to determine the parameters critical for activity versus ACE and NEP in vitro.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

BMS-196085: A potent and selective full agonist of the human β3 adrenergic receptor

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

A general synthesis of dioxolenone prodrug moieties

Abstract A general method for the synthesis of dioxolenone prodrug moieties from appropriately substituted β-ketoesters is described. This novel and versatile sequence allows for the synthesis of alkyl- or aryl-substituted dioxolenone alcohols 8 or bromides 9 . Coupling of the bromides 9 to prepare bis-dioxolenone phosphonate prodrug esters is also presented.

DUAL METALLOPROTEASE INHIBITORS. III: UTILIZATION OF BICYCLIC AND MONOCYCLIC DIAZEPINONE BASED MERCAPTOACETYLS

Abstract A series of bicyclic and monocyclic diazepinones were incorporated as conformationally restricted dipeptide surrogates in mercaptoacetyl dipeptide dual-acting ACE/NEP inhibitors. A comparison was made between these two classes of compounds as well as with the previously disclosed ACE/NEP inhibitor 1. Compound 2a was found to exhibit high potency versus both enzymes in vitro as well as in vivo.

Solid phase synthesis of 1,5-diarylpyrazole-4-carboxamides: discovery of antagonists of the CB-1 receptor.

We have developed a solid phase synthesis route to 1,5-substituted pyrazole-4-carboxamides with three diversity points aimed at the discovery of new compounds as potential G-Protein coupled receptor (GPCR) ligands. The new chemistry involves acylation of a resin bound secondary amine with a β-ketoester via transamidation, conversion of the resulting β-ketoamide to the corresponding vinylogous amide, pyrazole formation upon reaction with a aryl hydrzine, and cleavage of the product from the resin. Using the reported methodology, we describe the syntheses of multiple arrays of pyrazoles that were used collectively to construct a library of more than 1000 analogues. Several members of this library displayed submicromolar antagonist activities at the cannabinoid subtype 1 (CB-1) receptor.