Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists.

Autor: Mercer SE; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Bristol Myers Squibb, Cambridge, MA 02142, United States. Electronic address: stephen.mercer@bms.com., Chaturvedula PV; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Spectrum Pharmaceuticals, Irvine, CA 92618, United States., Conway CM; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, United States., Cook DA; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Medtronic, North Haven, CT 06473, United States., Davis CD; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Amgen, Inc. Thousand Oaks, CA 91320, United States., Pin SS; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Cerevel Therapeutics Cambridge, MA 02141, United States., Macci R; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Thermo Fisher Scientific, Branford, CT 06405, United States., Schartman R; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Preformulation Solutions, LLC. North Ridgeville, OH 44039, United States., Signor LJ; Bristol-Myers Squibb, Wallingford, CT 06492, United States., Widmann KA; Bristol-Myers Squibb, Wallingford, CT 06492, United States., Whiterock VJ; Bristol-Myers Squibb, Wallingford, CT 06492, United States., Chen P; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Bristol Myers Squibb, Lawrenceville, NJ 08543, United States., Xu C; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Amgen, Inc. Thousand Oaks, CA 91320, United States., Herbst JJ; Bristol-Myers Squibb, Wallingford, CT 06492, United States., Kostich WA; Bristol-Myers Squibb, Wallingford, CT 06492, United States; National Multiple Sclerosis Society, New York, NY 10017, United States., Thalody G; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Preformulation Solutions, LLC. North Ridgeville, OH 44039, United States., Macor JE; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Sanofi, Waltham, MA 02451, United States., Dubowchik GM; Bristol-Myers Squibb, Wallingford, CT 06492, United States; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Jan 01; Vol. 31, pp. 127624. Date of Electronic Publication: 2020 Oct 21.
DOI: 10.1016/j.bmcl.2020.127624
Abstrakt: Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP K i  = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (F PO  = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP K i  = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat F PO  = 17%).
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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