Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
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- 作者：Annapurna Pendri ; Dharmpal S. Dodd ; Jing Chen ; Mary Ellen Cvijic ; Liya Kang ; Rose A. Baska ; Kenneth E. Carlson ; Neil T. Burford ; Chongqing Sun ; William R. Ewing ; Samuel W. Gerritz
- 刊名：ACS Combinatorial Science
- 出版年：2012
- 出版时间：March 12, 2012
- 年：2012
- 卷：14
- 期：3
- 页码：197-204
- 全文大小：348K
- 年卷期：v.14,no.3(March 12, 2012)
- ISSN：2156-8944
文摘
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 尾-ketoester via transamidation, conversion of the resulting 尾-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.