RESUMEN
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Asunto(s)
Indoles/química , Indoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Cristalografía por Rayos X , Indazoles/química , Indazoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/química , Fosforilación , Relación Estructura-ActividadRESUMEN
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Triazoles/química , Triazoles/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Modelos Moleculares , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Ratas , Relación Estructura-Actividad , Triazoles/síntesis químicaRESUMEN
A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC(50) of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.
Asunto(s)
4-Quinolonas/farmacología , Descubrimiento de Drogas , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , 4-Quinolonas/síntesis química , 4-Quinolonas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.
Asunto(s)
Amidas/química , Antivirales/síntesis química , Inhibidores Enzimáticos/síntesis química , Hepacivirus/efectos de los fármacos , Tiofenos/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacología , Antivirales/química , Antivirales/farmacología , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Proteínas no Estructurales Virales/metabolismoRESUMEN
Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Indoles/síntesis química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Piridinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Enlace de Hidrógeno , Técnicas In Vitro , Indoles/química , Inyecciones Intravenosas , Proteína Quinasa 14 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/química , Modelos Moleculares , Unión Proteica , Isoformas de Proteínas , Piridinas/química , Piridinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Based on torsion angle distributions of frequently occurring substructures, conformation preferences of druglike molecules are presented, accompanied by a review of the relevant literature. First, the relevance of the Cambridge Structural Database (CSD) for drug design is demonstrated by comparing substructures present in compounds entering clinical trials with those found in the CSD and protein-bound ligands in the Protein Data Bank (PDB). Next, we briefly highlight preferred conformations of elementary acyclic systems, followed by a discussion of sulfonamide conformations. Due to their central role in medicinal chemistry, we discuss properties of aryl ring substituents in depth, including biaryl systems and systems of two aryl rings connected by two acyclic bonds. For a subset of torsion motifs, we also compare torsion angle histograms derived from CSD structures with those derived from ligands in the PDB. Furthermore, selected properties of some six- and seven-membered ring systems are discussed. The article closes with a section on attractive sulfur-oxygen contacts.