Discovery of CVN636 : A Highly Potent, Selective, and CNS Penetrant mGluR 7 Allosteric Agonist.

Autor: Dickson L; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Teall M; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Chevalier E; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Cheung T; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Liwicki GM; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Mack S; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Stephenson A; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., White K; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Fosbeary R; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Harrison DC; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Brice NL; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Doyle K; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Ciccocioppo R; School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino 62032, Italy., Wu C; WuXi Apptec Limited, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Almond S; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Patel TR; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Mitchell P; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Barnes M; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Ayscough AP; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Dawson LA; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Carlton M; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.; Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Bürli RW; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Mar 02; Vol. 14 (4), pp. 442-449. Date of Electronic Publication: 2023 Mar 02 (Print Publication: 2023).
DOI: 10.1021/acsmedchemlett.2c00529
Abstrakt: The low affinity metabotropic glutamate receptor mGluR 7 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 mGluR 7 agonists. Of particular interest is the chromane CVN636 , a potent (EC 50 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR 7 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 mGluR 7 and glutamatergic dysfunction.
Competing Interests: The authors declare no competing financial interest.
(© 2023 American Chemical Society.)
Databáze: MEDLINE
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