2. Academic Validation
  3. Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists

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

  • Bioorg Med Chem Lett. 2021 Jan 1;31:127624. doi: 10.1016/j.bmcl.2020.127624.
Stephen E Mercer 1,  Prasad V Chaturvedula 2,  Charles M Conway 3,  Deborah A Cook 4,  Carl D Davis 5,  Sokhom S Pin 6,  Robert Macci 7,  Richard Schartman 8,  Laura J Signor 9,  Kimberly A Widmann 9,  Valerie J Whiterock 9,  Ping Chen 10,  Cen Xu 5,  John J Herbst 9,  Walter A Kostich 11,  George Thalody 8,  John E Macor 12,  Gene M Dubowchik 3
Affiliations

Affiliations

  • 1 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Bristol Myers Squibb, Cambridge, MA 02142, United States. Electronic address: stephen.mercer@bms.com.
  • 2 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Spectrum Pharmaceuticals, Irvine, CA 92618, United States.
  • 3 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, United States.
  • 4 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Medtronic, North Haven, CT 06473, United States.
  • 5 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Amgen, Inc. Thousand Oaks, CA 91320, United States.
  • 6 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Cerevel Therapeutics Cambridge, MA 02141, United States.
  • 7 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Thermo Fisher Scientific, Branford, CT 06405, United States.
  • 8 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Preformulation Solutions, LLC. North Ridgeville, OH 44039, United States.
  • 9 Bristol-Myers Squibb, Wallingford, CT 06492, United States.
  • 10 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Bristol Myers Squibb, Lawrenceville, NJ 08543, United States.
  • 11 Bristol-Myers Squibb, Wallingford, CT 06492, United States; National Multiple Sclerosis Society, New York, NY 10017, United States.
  • 12 Bristol-Myers Squibb, Wallingford, CT 06492, United States; Sanofi, Waltham, MA 02451, United States.
PMID: 33096162 DOI: 10.1016/j.bmcl.2020.127624
Abstract

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 Ki = 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 (FPO = 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 Ki = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat FPO = 17%).

Keywords

Calcitonin gene-related peptide; Caprolactam; Indazole; Migraine.

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