Strategies to lower the Pgp efflux liability in a series of potent indole azetidine MCHR1 antagonists

…, B Chen, EM Eldemenky, G Ma, M Packiarajan…

Index: Lu, Kai; Jiang, Yu; Chen, Bin; Eldemenky, Eman M.; Ma, Gil; Packiarajan, Mathivanan; Chandrasena, Gamini; White, Andrew D.; Jones, Kenneth A.; Li, Boshan; Hong, Sang-Phyo Bioorganic and Medicinal Chemistry Letters, 2011 , vol. 21, # 18 p. 5310 - 5314

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Citation Number: 8

Abstract

A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify 1-dihydroindolyl azetidine ...