Discovery of (R)-4-(8-Fluoro-2-oxo-1, 2-dihydroquinazolin-3 (4 H)-yl)-N-(3-(7-methyl-1 H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl) piperidin-1-yl) propan-2-yl) …

…, R Denton, X Han, R Macci, NR Mathias…

Index: 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. Journal of Medicinal Chemistry, 2008 , vol. 51, # 16 p. 4858 - 4861

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Citation Number: 40

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 ...