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

Autor:	Neil Mathias, Sokhom S. Pin, Xiaojun Han, Paul Moench, John E. Macor, Richard Schartman, Charles M. Conway, Chaturvedula Prasad, Rex Denton, Kimberly A. Widmann, Laura J. Signor, Gene M. Dubowchik, Deborah A. Cook, Andrew P. Degnan, George Thalody, Robert Macci, Carl D. Davis, Shelly X. Ren, Cen Xu
Rok vydání:	2008
Předmět:	Bicyclic molecule medicine.drug_class Stereochemistry Chemistry Carboxamide Biological activity Calcitonin gene-related peptide Chemical synthesis chemistry.chemical_compound In vivo Drug Discovery medicine Molecular Medicine Piperidine Ex vivo
Zdroj:	Journal of Medicinal Chemistry. 51:4858-4861
ISSN:	1520-4804 0022-2623
DOI:	10.1021/jm800546t
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::fa440795b5aa2edcd0d1f4a3cb63ab67 https://doi.org/10.1021/jm800546t Zobrazit plný text záznamu