RESUMO
An oxidation product (5) formed during the synthesis of BIBN-4096BS (1) was found to be a potent CGRP antagonist (IC50=0.11nM). While 5 was found to be ten-fold less potent than 1, another analog 8 with lower molecular weight containing the oxidized fragment demonstrated twenty-fold higher activity than its parent 7. Alternative conditions which preclude the formation of the oxidation product are described. The activities of 1, 5, 7 and 8 in functional cAMP assay are also discussed.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Piperazinas/química , Quinazolinas/química , Bioensaio , Concentração Inibidora 50 , Estrutura Molecular , Oxirredução , Piperazinas/síntese química , Piperazinas/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologiaRESUMO
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow.
Assuntos
Amidas/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indazóis/química , Quinolonas/química , Administração Intranasal , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Células CACO-2 , Callithrix , Vasos Coronários/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Face/irrigação sanguínea , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Coelhos , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologiaRESUMO
We report the synthesis of rigid spirocyclic systems as conformationally constrained variants of the Ala-Phe-NH(2) dipeptide amide C-terminus of the calcitonin gene-related peptide (CGRP). CGRP receptor antagonists containing these moieties displayed potent affinity, functional antagonism and excellent oxidative stability. Structure-activity relationship studies demonstrated the relative importance of hydrogen bond donor/acceptor functionalities and the preferred orientation of an aromatic ring. Antagonists showed potent and full reversal of CGRP-induced dilation of ex vivo human intracranial arteries.
