The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2.
Bioorg Med Chem Lett
; 23(6): 1870-3, 2013 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-23402880
ABSTRACT
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%).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tirosina
/
Quinazolinonas
/
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina
/
Aminoácidos
/
Indazóis
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article