RESUMEN
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.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Piperazinas/química , Quinazolinas/química , Bioensayo , Concentración 50 Inhibidora , Estructura Molecular , Oxidación-Reducción , Piperazinas/síntesis química , Piperazinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacologíaRESUMEN
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.
Asunto(s)
Amidas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Indazoles/química , Quinolonas/química , Administración Intranasal , Amidas/farmacología , Amidas/uso terapéutico , Animales , Células CACO-2 , Callithrix , Vasos Coronarios/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Cara/irrigación sanguínea , Humanos , Indazoles/farmacología , Indazoles/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Quinolonas/farmacología , Quinolonas/uso terapéutico , Conejos , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/patologíaRESUMEN
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.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Compuestos de Espiro/química , Diseño de Fármacos , Enlace de Hidrógeno , Estructura Molecular , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.