Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box
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- 作者：Hong Huang ; Andrew P. Degnan ; Anand Balakrishnan ; Amy Easton ; Michael Gulianello ; Yanling Huang ; Michele Matchett ; Gail Mattson ; Regina Miller ; Kenneth S. Santone ; Arun Senapati ; Eric E. Shields ; Digavalli V. Sivarao ; Lawrence B. Snyder ; Ryan Westphal ; Valerie J. Whiterock ; Fukang Yang ; Joanne J. Bronson ; John E. Macor
- 关键词：mGluR5 ; mGlu5 ; Positive allosteric modulator ; Silent allosteric modulator ; Schizophrenia ; Cognition
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：1 September 2016
- 年：2016
- 卷：26
- 期：17
- 页码：4165-4169
- 全文大小：1439 K
文摘
Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl boldFont">22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.