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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 6; pp. 1870 - 1873
• Main Authors: Han, Xiaojun, Civiello, Rita L., Conway, Charles M., Cook, Deborah A., Davis, Carl D., Degnan, Andrew P., Jiang, Xiang-Jun, Macci, Robert, Mathias, Neil R., Moench, Paul, Pin, Sokhom S., Schartman, Richard, Signor, Laura J., Thalody, George, Tora, George, Whiterock, Valerie, Xu, Cen, Macor, John E., Dubowchik, Gene M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-03-2013
• Subjects: Administration, Intranasal; Amino Acids - chemical synthesis; Amino Acids - chemistry; Amino Acids - pharmacokinetics; Animals; antagonists; Benzoxazoles - chemistry; bioavailability; Biological Availability; blood flow; calcitonin; Calcitonin gene-related peptide (CGRP); CGRP receptor antagonist; CYP 3A4 inhibition; Half-Life; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacokinetics; Migraine headache; nose; Protein Binding; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacokinetics; Rabbits; Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors; Receptors, Calcitonin Gene-Related Peptide - metabolism; solubility; Structure-Activity Relationship; toxicology; tyrosine; Tyrosine - chemistry; Tyrosine surrogates; CGRP receptor antagonist; Tyrosine surrogates; Migraine headache; Calcitonin gene-related peptide (CGRP); CYP 3A4 inhibition
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.01.011

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%).