Debnath Bhuniya

Novel pyrazole-3-carboxamide derivatives as cannabinoid-1 (CB1) antagonists: Journey from non-polar to polar amides

The synthesis and biological evaluation of novel pyrazole-3-carboxamide derivatives as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced. In general, a range of modifications were well tolerated. Several molecules with high polar surface area were also identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is exemplified with a lead compound from this series.

Porcine liver esterase catalyzed kinetic resolution of baylis-hillman (B-H) adducts

Abstract Esterase from porcine liver smoothly resolves varieties of racemic 2-methylene-3-substituted-3-hydroxypropanoates (B-H adducts) to obtain the corresponding unreacted esters in very good to excellent ee (94 to >99%, seven examples) and hydrolyzed acids in good ee (58–75%). Substitution in B-H adducts, chosen for resolution, are funtionalized phenyl, thiophen-3-yl, cinnamyl, and alkyl groups. †DRL Pub. No. 232. Dedicated to Dr. A. Venkateswarlu on the occasion of his 63rd birth anniversary

Synthesis of novel oxime functionalized aldol products via michael addition of oximes onto baylis-hillman adducts

Abstract Triphenylphosphine‐catalyzed Michael addition of oximes 2 onto Baylis–Hillman (B‐H) adducts 1 led to an easy access to a novel class of oxime functionalized aldol products 3. This demonstrates the first use of an oxygen‐centered nucleophile in Michael addition to B‐H adducts, without touching any other functional group. Deprotection of oxime in 3 was further demonstrated using molecular hydrogen (1xa0atm) and 10% Pd/C (cat.) to furnish functionalized 1,3‐diols 4 as potentially useful synthons with optional backbone choice (R3 and EWG). DRL Publication No. 354. Part of these results was presented at Pharmacophore 2004, January 16–17, 2004, an international symposium organized by Dr. Reddys Laboratories Ltd. on the occasion of its achievement in drug discovery.

Identification of a Pharmacological Inducer of Lipoic Acid Synthase that Impacts Mitochondrial Function: Metabolic Benefits and Body Weight Loss without Changes in Caloric Intake

Objective: Lipoic Acid Synthase (LASY) was recently shown to play a critical role in inflammation, mitochondrial function and insulin resistance. In this study using a pharmacological inducer of LASY as a tool, we studied the effects of LASY induction in vivo in rodent models of obesity and type 2 diabetes. nMethods: We identified a small molecule that increases LASY mRNA and lipoic acid levels in vitro. Effect of the inducer (compound 1) on body weight, food intake, energy expenditure and metabolic parameters was studied in rodent models of genetic and diet-induced obesity. nResults: Compound 1 was identified as a transcriptional inducer of LASY. In vitro, compound 1 increased LASY mRNA expression, mitochondrial lipoic acid levels and improved mitochondrial function in cultured skeletal muscle cells. LASY mRNA and lipoic acid levels were significantly increased in skeletal muscle and adipose tissue of animals treated with compound 1. In genetic and diet-induced rodent models of obesity, treatment with compound 1 significantly reduced body weight gain and fat mass without changes in food intake. Whole-animal calorimetry revealed that compound 1-treated animals had a significant increase in energy expenditure over vehicle control. Compound 1 treatment was also accompanied by improvements in plasma metabolic parameters and increase in lean mass. nConclusion: Our data suggests that the benefical effects of compound 1 are mediated by increase in mitochondrial lipoic acid levels, although general effects on mitochondrial function cannot be ruled out. These results establish the in vivo relevance of LASY induction and show the potential of a peripheral mediated approach for achieving many of the desired effects in treating obesity. Future studies focusing on the mechanism(s) by which compound 1 exerts its beneficial effects will help to reveal if these benefits are specific to LASY induction or are due to non-specific effects on mitochondrial function.