Saleem Ahmad

(3R,5S,E)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with Reduced Myotoxicity Potential

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

An efficient and diastereoselective [2+2] cycloaddition : convenient and enantioselective route to trans-2',3'-dihydroxymethylcyclobutane nucleoside analogs

Abstract An efficient route to (2 S - trans )-2,3-bis[(benzoyloxy)methyl]cyclobutanone ( 3a ), a key intermediate in the synthesis of cyclobutane nucleoside analogs, via a novel asymmetric [2+2] cycloaddition, is described.

Pyrazole-based sulfonamide and sulfamides as potent inhibitors of mammalian 15-lipoxygenase.

A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.

Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.

Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.

Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate.

Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).

Vicarious nucleophilic substitution of 1-benzyl-5-nitroimidazole, application to the synthesis of 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one

Reaction of 1-benzyl-5-nitroimidazole with carbanion generated from chloroform and potassium tert-butoxide afforded 1-benzyl-4-dichloromethyl-5-nitroimidazole in 72% yield. This vicarious nucleophilic substitution reaction was successfully applied to the synthesis of 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one, an important intermediate in the synthesis of natural and biologically active compounds.

α-hydroxyamide derived aminodiols as potent inhibitors of hiv protease

Abstract A novel series of HIV protease inhibitors has been prepared. Replacement of the P2 carbamate of compound 1 [IC50 = 125 nM] with an α-hydroxy amide moiety results in a significant increase in anti-HIV protease activity [e. g., compound 25a; IC50 = 15 nM]. Furthermore, isomers with (R) absolute configuration at the P2 site show greater inhibitory activity than the corresponding (S)-isomers. A proposed binding mode based on molecular modeling is used to rationalize the structure-activity relationships.

Optically active fluorinated cyclobutane nucleoside analogs with potent anti-herpes activity

Abstract The synthesis and antiherpes activity of several optically active 4′-fluoro-2′,3′-dihydroxymethylcyclobutyl nucleoside analogs are described. A key synthetic step is the diastereoselective [2+2] cycloaddition of a novel fluoroketene acetal with (−)-dimethyl fumarate.

A new facile method for the stereoselective synthesis of trans-2-aryl-3,3-dimethylcyclopropane-1-carboxylic acids

Abstract A new facile method for the preparation of trans -2-aryl-3,3-dimethylcyclopropane-1-carboxylic acids was developed. The new method involved [2+2]-cycloaddition of styrenes with N , N ,2-trimethylpropionamide followed by bromination and rearrangement of the resulting 3-aryl-2,2-dimethylcyclobutanones, affording the title compounds in two steps in 60–84% overall yields.

Aminodiol HIV protease inhibitors. 2. 1,1-Dimethyl-2-hydroxyethyl carbamate derivatives with enhanced potency

Abstract A series of BOC-modified analogs of the aminodiol HIV protease inhibitor BMS-182193 (1) was prepared and tested for inhibitory activity against the enzyme and the virus in cell culture. The hydroxymodified analogs, 5 and 20 , showed enhanced potency against the protease and 5 was more active than 1 against the virus in cell culture.