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-carbox

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：August 28, 2008
• 年：2008
• 卷：51
• 期：16
• 页码：4858-4861
• 全文大小：171K
• 年卷期：v.51,no.16(August 28, 2008)
• ISSN：1520-4804

文摘

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.