Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists

详细信息	查看全文 | 推荐本文 |

• 作者：Sanjita Sasmal^a ; Gade Balaji^a ; Hariprasada R. Kanna Reddy^a ; D. Balasubrahmanyam^a ; Gujjary Srinivas^a ; ShivaKumar Kyasa^a ; Pradip K. Sasmal^a ; ^&dagger ; ; ^{pradipks@drreddys.com} ; ^{sasmalpk@yahoo.co.in} ; Ish Khanna^a ; Rashmi Talwar^a ; J. Suresh^a ; Vikram P. Jadhav^a ; Syed Muzeeb^a ; Dhanya Shashikumar^a ; K. Harinder Reddy^a ; V.J. Sebastian^a ; Thomas M. Frimurer^b ; Ø ; ystein Rist^b ; Lisbeth Elster^b ; Thomas H&ouml ; gberg^b ; ^&Dagger ;
• 关键词：Melanin concentrating hormone (MCH) ; MCHR1 antagonists ; MCH receptor ensembles ; Obesity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 May, 2012
• 卷：22
• 期：9
• 页码：3157-3162
• 文件大小：1657 K

摘要

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the 尾2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.