title: Solid phase synthesis of 1,5-diarylpyrazole-4-carboxamides: discovery of antagonists of the CB-1 receptor.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, United States. annapurna.pendri@bms.com
authors.forename: Annapurna
authors.initials: A
authors.lastname: Pendri
authors.forename: Dharmpal S
authors.initials: DS
authors.lastname: Dodd
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.forename: Liya
authors.initials: L
authors.lastname: Kang
authors.forename: Rose A
authors.initials: RA
authors.lastname: Baska
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Neil T
authors.initials: NT
authors.lastname: Burford
authors.forename: Chongqing
authors.initials: C
authors.lastname: Sun
authors.forename: William R
authors.initials: WR
authors.lastname: Ewing
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Gerritz
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000577:Amides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1