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

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%).

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Han X,Civiello RL,Conway CM,Cook DA,Davis CD,Degnan AP,Jiang XJ,Macci R,Mathias NR,Moench P,Pin SS,Schartman R,Signor LJ,Thalody G,Tora G,Whiterock V,Xu C,Macor JE,Dubowchik GM

doi

10.1016/j.bmcl.2013.01.011

subject

Has Abstract

pub_date

2013-03-15 00:00:00

pages

1870-3

issue

6

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(13)00033-4

journal_volume

23

pub_type

杂志文章

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