Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist

Louise Dickson; Martin Teall; Elodie Chevalier; Toni Cheung; Gemma M Liwicki; Stephen Mack; Anne Stephenson; Kathryn White; Richard Fosbeary; David C Harrison; Nicola L Brice; Kevin Doyle; Roberto Ciccocioppo; Chaobo Wu; Sarah Almond; Toshal R Patel; Philip Mitchell; Matt Barnes; Andrew P Ayscough; Lee A Dawson; Mark Carlton; Roland W Bürli

doi:10.1021/acsmedchemlett.2c00529

Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR₇ Allosteric Agonist

ACS Med Chem Lett. 2023 Mar 2;14(4):442-449. doi: 10.1021/acsmedchemlett.2c00529. eCollection 2023 Apr 13.

Authors

Louise Dickson^{1

2}, Martin Teall^{1

2}, Elodie Chevalier^{1

2}, Toni Cheung^{1

2}, Gemma M Liwicki², Stephen Mack², Anne Stephenson², Kathryn White², Richard Fosbeary^{1

2}, David C Harrison², Nicola L Brice^{1

2}, Kevin Doyle¹, Roberto Ciccocioppo³, Chaobo Wu⁴, Sarah Almond², Toshal R Patel², Philip Mitchell², Matt Barnes², Andrew P Ayscough^{1

2}, Lee A Dawson¹, Mark Carlton^{1

2}, Roland W Bürli¹

Affiliations

¹ Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.
² Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.
³ School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino 62032, Italy.
⁴ WuXi Apptec Limited, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.

Abstract

The low affinity metabotropic glutamate receptor mGluR₇ has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR₇ agonists. Of particular interest is the chromane CVN636, a potent (EC₅₀ 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR₇ compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR₇ and glutamatergic dysfunction.