RESUMEN
The biochemical basis for S9-dependent mutagenic response of the 5-HT(2C) receptor agonist and diazinylpiperazine derivative 1 in the Salmonella Ames assay involves P450-mediated bioactivation to DNA-reactive quinone-methide, aldehyde and nitrone intermediates. Mechanistic information pertaining to the metabolism of 1 was used in the design of diazinylpiperazine 5 to eliminate the safety liability. While 5 was negative in the Ames assay, the compound retained the ability of 1 to form certain electrophilic intermediates. Plausible hypotheses that can collectively account for the differences in mutagenic response of the two piperazine analogs are discussed.
Asunto(s)
Química Farmacéutica/métodos , Piperazinas/química , Agonistas del Receptor de Serotonina 5-HT2 , Amidas/química , Cromatografía/métodos , Diseño de Fármacos , Modelos Químicos , Mutagénesis , Pruebas de Mutagenicidad , Mutágenos , Mutación , NADP/química , Piperazina , Reproducibilidad de los Resultados , Salmonella/metabolismoRESUMEN
The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Oxazoles/química , Piridinas/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/química , Química Farmacéutica , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Solubilidad , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.
Asunto(s)
Bencimidazoles/química , Piridinas/química , Triazoles/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/química , Bencimidazoles/síntesis química , Sitios de Unión , Cristalografía por Rayos X , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Imitación Molecular , Estructura Molecular , Unión Proteica , Piridinas/síntesis química , Relación Estructura-Actividad Cuantitativa , Electricidad Estática , Triazoles/síntesis químicaRESUMEN
The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.
Asunto(s)
Metaloproteinasa 1 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Ácidos Hidroxámicos/química , Metaloproteinasa 13 de la Matriz , Metaloproteinasas de la Matriz/metabolismo , Inhibidores de Proteasas/farmacología , Piranos/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The synthesis and in vitro p38 alpha activity of a novel series of benzimidazolone inhibitors is described. The p38 alpha SAR is consistent with a mode of binding wherein the benzimidazolone carbonyl serves as the H-bond acceptor to Met109 of p38 alpha in a manner analogous to the pyridine nitrogen of prototypical pyridylimidazole p38 inhibitors. Potent p38 alpha activity comparable to that of several previously reported p38 inhibitors is observed for this novel chemotype.