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

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 outs...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-08, Vol.51 (16), p.4858-4861
Main Authors: Degnan, Andrew P, Chaturvedula, Prasad V, Conway, Charles M, Cook, Deborah A, Davis, Carl D, Denton, Rex, Han, Xiaojun, Macci, Robert, Mathias, Neil R, Moench, Paul, Pin, Sokhom S, Ren, Shelly X, Schartman, Richard, Signor, Laura J, Thalody, George, Widmann, Kimberly A, Xu, Cen, Macor, John E, Dubowchik, Gene M
Format: Article
Language:English
Subjects:
Administration, Intranasal
Animals
Biological Availability
Calcitonin Gene-Related Peptide - antagonists & inhibitors
Callithrix
Coronary Vessels - drug effects
Face - blood supply
Humans
Indazoles - administration & dosage
Indazoles - chemical synthesis
Indazoles - therapeutic use
Migraine Disorders - drug therapy
Quinazolinones - administration & dosage
Quinazolinones - chemical synthesis
Quinazolinones - therapeutic use
Rabbits
Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors
Regional Blood Flow - drug effects
Vasodilation - drug effects
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Summary: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 bioavailablity in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800546t