Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead.
Bioorg Med Chem Lett
; 16(10): 2595-8, 2006 May 15.
Article
em En
| MEDLINE
| ID: mdl-16527483
ABSTRACT
High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor-acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor K(i)=44nM and IC(50)=38nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzodiazepinonas
/
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Estados Unidos