Design and Synthesis of Diazatricyclodecane Agonists of the G-Protein-Coupled Receptor 119

详细信息    查看全文

• 作者：Etzer Darout ; Ralph P. Robinson ; Kim F. McClure ; Matthew Corbett ; Bryan Li ; Andrei Shavnya ; Melissa P. Andrews ; Christopher S. Jones ; Qifang ; Li ; Martha L. Minich ; Vincent Mascitti ; Cristiano R. W. Guimar茫es ; Michael J. Munchhof ; Kevin B. Bahnck ; Cuiman Cai ; David A. Price ; Spiros Liras ; Paul D. Bonin ; Peter Cornelius ; Ruduan Wang ; Victoria Bagdasarian ; Colleen P. Sobota ; Sam Hornby ; Victoria M. Masterson ; Reena M. Joseph ; Amit S. Kalgutkar ; Yue Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：301-319
• 全文大小：548K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.13,7]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann鈥揕枚ffler鈥揊reytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the 鈥渁gonist conformation鈥?as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.