Discovery of selective biaryl ethers as PDE10A inhibitors: Improvement in potency and mitigation of Pgp-mediated efflux

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• 作者：Robert M. Rzasa^a ; ^{rrzasa@amgen.com} ; Essa Hu^a ; Shannon Rumfelt^a ; Ning Chen^a ; Kristin L. Andrews^c ; Samer Chmait^c ; James R. Falsey^a ; Wenge Zhong^a ; Adrie D. Jones^d ; Amy Porter^b ; Steven W. Louie^e ; Xiaoning Zhao^d ; James J.S. Treanor^b ; Jennifer R. Allen^a
• 关键词：Phosphodiesterase ; PDE10A ; Inhibitors ; Pgp-mediated efflux ; Schizophrenia
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：15 December, 2012
• 年：2012
• 卷：22
• 期：24
• 页码：7371-7375
• 全文大小：1900 K

文摘

We report the discovery of a novel series of biaryl ethers as potent and selective PDE10A inhibitors. Structure-activity studies improved the potency and decreased Pgp-mediated efflux found in the initial compound 4. X-ray crystallographic studies revealed two novel binding modes to the catalytic site of the PDE10A enzyme.