2. Academic Validation
  3. Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure

Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure

  • J Med Chem. 2008 Aug 28;51(16):4858-61. doi: 10.1021/jm800546t.
Andrew P Degnan 1,  Prasad V Chaturvedula,  Charles M Conway,  Deborah A Cook,  Carl D Davis,  Rex Denton,  Xiaojun Han,  Robert Macci,  Neil R Mathias,  Paul Moench,  Sokhom S Pin,  Shelly X Ren,  Richard Schartman,  Laura J Signor,  George Thalody,  Kimberly A Widmann,  Cen Xu,  John E Macor,  Gene M Dubowchik
Affiliations

Affiliation

  • 1 Department of Neuroscience Chemistry, Bristol-Myers Squibb Research & Development,Wallingford, Connecticut 06492, USA. andrew.degnan@bms.com
PMID: 18665579 DOI: 10.1021/jm800546t
Abstract

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chemistry leads suffered from modest potency, significant CYP3A4 inhibition, and poor aqueous solubility. Herein, we describe the optimization of these leads to give 4 (BMS-694153), a molecule with outstanding potency, a favorable predictive toxicology profile, and remarkable aqueous solubility. Compound 4 has good intranasal bioavailability in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models.

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