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

Abstract Various substituted indazoleand benzoxazolone amino acids were investigated as d -tyrosine surrogates in highly potent CGRP receptorantagonists. Compound 3 , derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazoleanalog 1 . When dosed at 0.03 mg/kg SC, compound 2 (a racemic mixtureof 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 toxicologyprofile, and good aqueous solubility. When dosed as a nasal sprayin rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%).