RESUMEN
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.
Asunto(s)
Benzoatos/farmacología , Indoles/farmacología , Dolor/tratamiento farmacológico , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Artritis/tratamiento farmacológico , Benzoatos/química , Benzoatos/uso terapéutico , Células Cultivadas , Perros , Descubrimiento de Drogas , Estabilidad de Medicamentos , Hepatocitos , Humanos , Indoles/química , Indoles/uso terapéutico , Inflamación/tratamiento farmacológico , Farmacocinética , Ratas , Subtipo EP4 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antiinflamatorios/síntesis química , Hidrazinas/síntesis química , Receptores de Interleucina-8B/antagonistas & inhibidores , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Células CHO , Quimiotaxis/efectos de los fármacos , Cricetinae , Cricetulus , Diseño de Fármacos , Humanos , Hidrazinas/química , Hidrazinas/farmacología , Interleucina-8/metabolismo , Microsomas Hepáticos/metabolismo , Ratas , Receptores de Interleucina-8B/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Analgésicos/síntesis química , Benzoatos/síntesis química , Ciclopropanos/síntesis química , Antagonistas de Prostaglandina/síntesis química , Receptores de Prostaglandina E/metabolismo , Tiofenos/síntesis química , Analgésicos/química , Analgésicos/farmacocinética , Animales , Benzoatos/química , Benzoatos/farmacocinética , Ciclopropanos/química , Ciclopropanos/farmacocinética , Semivida , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Dolor/tratamiento farmacológico , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Prostaglandina E/antagonistas & inhibidores , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacocinéticaRESUMEN
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.