2. Academic Validation
  3. Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box

Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box

  • Bioorg Med Chem Lett. 2016 Sep 1;26(17):4165-9. doi: 10.1016/j.bmcl.2016.07.065.
Hong Huang 1,  Andrew P Degnan 1,  Anand Balakrishnan 1,  Amy Easton 1,  Michael Gulianello 1,  Yanling Huang 1,  Michele Matchett 1,  Gail Mattson 1,  Regina Miller 1,  Kenneth S Santone 1,  Arun Senapati 1,  Eric E Shields 1,  Digavalli V Sivarao 1,  Lawrence B Snyder 1,  Ryan Westphal 1,  Valerie J Whiterock 1,  Fukang Yang 1,  Joanne J Bronson 1,  John E Macor 1
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
PMID: 27496211 DOI: 10.1016/j.bmcl.2016.07.065
Abstract

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 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.

Keywords

Cognition; Positive allosteric modulator; Schizophrenia; Silent allosteric modulator; mGlu5; mGluR5.

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