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.

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.

• Authors: Andrew P Degnan, 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 16 Pg. 4858-61 (Aug 28 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18665579 (Publication Type: Journal Article)

Chemical References

• 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
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Indazoles
• Quinazolinones
• Calcitonin Gene-Related Peptide

Topics

• Administration, Intranasal
• Animals
• Biological Availability
• Calcitonin Gene-Related Peptide (antagonists & inhibitors)
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Callithrix
• Coronary Vessels (drug effects)
• Face (blood supply)
• Humans
• Indazoles (administration & dosage, chemical synthesis, therapeutic use)
• Migraine Disorders (drug therapy)
• Quinazolinones (administration & dosage, chemical synthesis, therapeutic use)
• Rabbits
• Regional Blood Flow (drug effects)
• Vasodilation (drug effects)