The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2.

The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2.

Bioorganic & medicinal chemistry letters (2013-02-14)

Xiaojun Han, 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

PMID23402880

摘要

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 0.03mg/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 105min. 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%).