Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor

• Published in: ACS combinatorial science Vol. 14; no. 3; pp. 197 - 204
• Main Authors: Pendri, Annapurna, Dodd, Dharmpal S, Chen, Jing, Cvijic, Mary Ellen, Kang, Liya, Baska, Rose A, Carlson, Kenneth E, Burford, Neil T, Sun, Chongqing, Ewing, William R, Gerritz, Samuel W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.03.2012; Amer Chemical Soc
• Subjects: Amides - chemistry; Amides - pharmacology; Aromatic compounds; Arrays; Chemistry; Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary; Combinatorial analysis; Drug Discovery; Inhibitory Concentration 50; Libraries; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Polymers; Protein Binding - drug effects; Pyrazole; Pyrazoles - chemistry; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - chemistry; Receptors; Resins; Science & Technology; Solid phase synthesis; Solid-Phase Synthesis Techniques; solid phase synthesis; GPCR ligands; privileged scaffolds; pyrazole-4- carboxamide; ASSISTED SYNTHESIS; PYRAZOLES; DRUG DISCOVERY; 5-AMINOPYRAZOLES; COMPREHENSIVE SURVEY; ISOXAZOLES; COMBINATORIAL LIBRARY SYNTHESIS; REGIOSELECTIVE SYNTHESIS; pyrazole-4-carboxamide; INHIBITORS; DERIVATIVES
• ISSN: 2156-8952; 2156-8944
• DOI: 10.1021/co200147y

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.