RESUMO
The discovery of a highly potent and selective EP(4) antagonist MF-766 is discussed. This N-benzyl indole derivative exhibits good pharmacokinetic profile and unprecedented in vivo potency in the rat AIA model.
Assuntos
Benzoatos/farmacologia , Indóis/farmacologia , Dor/tratamento farmacológico , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Artrite/tratamento farmacológico , Benzoatos/química , Benzoatos/uso terapêutico , Células Cultivadas , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Hepatócitos , Humanos , Indóis/química , Indóis/uso terapêutico , Inflamação/tratamento farmacológico , Farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-AtividadeRESUMO
The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.
Assuntos
Analgésicos/síntese química , Benzoatos/síntese química , Ciclopropanos/síntese química , Antagonistas de Prostaglandina/síntese química , Receptores de Prostaglandina E/metabolismo , Tiofenos/síntese química , Analgésicos/química , Analgésicos/farmacocinética , Animais , Benzoatos/química , Benzoatos/farmacocinética , Ciclopropanos/química , Ciclopropanos/farmacocinética , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Dor/tratamento farmacológico , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/antagonistas & inibidores , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacocinéticaRESUMO
We describe herein a novel series of 3-amino-4-hydrazine-cyclobut-3-ene-1,2-diones as potent and selective inhibitors against the CXCR2 chemokine receptor and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Furthermore, these alkyl-hydrazine series inhibitors such as 5b demonstrated acceptable metabolic stability when incubated in human and rat microsomes.
Assuntos
Anti-Inflamatórios/síntese química , Hidrazinas/síntese química , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Células CHO , Quimiotaxia/efeitos dos fármacos , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Hidrazinas/química , Hidrazinas/farmacologia , Interleucina-8/metabolismo , Microssomos Hepáticos/metabolismo , Ratos , Receptores de Interleucina-8B/metabolismo , Relação Estrutura-AtividadeRESUMO
PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.
