The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2
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- 作者：Xiaojun Han ; xiaojun.han@bms.com ; Rita L. Civiello ; Charles M. Conway ; Deborah A. Cook ; Carl D. Davis ; Andrew P. Degnan ; Xiang-Jun Jiang ; Robert Macci ; Neil R. Mathias ; Paul Moench ; Sokhom S. Pin ; Richard Schartman ; Laura J. Signor ; George Thalody ; George Tora ; Valerie Whiterock ; Cen Xu ; John E. Macor ; Gene M. Dubowchik
- 关键词：CGRP receptor antagonist ; Calcitonin gene-related peptide (CGRP) ; Migraine headache ; Tyrosine surrogates ; CYP 3A4 inhibition
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：15 March, 2013
- 年：2013
- 卷：23
- 期：6
- 页码：1870-1873
- 全文大小：1549 K
文摘
Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03 mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105 min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42 % ).