RESUMEN
A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Masculino , Microsomas Hepáticos/enzimología , Estructura Molecular , Piridazinas/química , Piridazinas/farmacología , Piridonas/química , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pironas/síntesis química , Pironas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Benzamidas/química , Modelos Animales de Enfermedad , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Macaca fascicularis , Masculino , Estructura Molecular , Piridonas , Pironas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/farmacologíaRESUMEN
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.
Asunto(s)
Antiinflamatorios/química , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Administración Oral , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Piridonas/síntesis química , Piridonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead 1, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compounds in which the phenoxy group was substituted at the 3, 4, or 5 positions. In general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency relative to 1, while analogues containing electron-donating or hydrogen bond accepting groups exhibited lower potency. Compounds with polar or strong electron-withdrawing groups also displayed lower potency. Replacement of the phenoxy ring in 1 with either simple aliphatic or cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better compounds, a representative series 4a-i was prepared as the chirally pure R(+) enantiomers, and from these, the 4-chloro-3-ethylphenoxy analogue was identified as a potent inhibitor of CETP activity in buffer (4a, IC50 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer 4a represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and biochemical characterization of 4a are reported along with its preliminary pharmacological assessment in animals.