RESUMEN
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Asunto(s)
Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , RatasRESUMEN
JNK2 and p38alpha are closely related mitogen-activated protein kinases that regulate various cellular activities and are considered drug targets for inflammatory diseases. We have determined the X-ray crystal structure of the clinical phase II p38alpha inhibitor BIRB796 bound to its off-target JNK2. This shows for the first time a JNK subfamily member in the DFG-out conformation. The fully resolved activation loop reveals that BIRB796 inhibits JNK2 activation by stabilizing the loop in a position that does not allow its phosphorylation by upstream kinases. The structure suggests that substituents at the BIRB796 morpholino group and modifications of the t-butyl moiety should further increase the p38alpha to JNK2 potency ratio. For the design of selective DFG-out binding JNK2 inhibitors, the binding pocket of the BIRB796 tolyl group may have the best potential.
Asunto(s)
Proteína Quinasa 9 Activada por Mitógenos/química , Proteínas Quinasas Activadas por Mitógenos/química , Naftalenos/química , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Cristalografía por Rayos X , Diseño de Fármacos , Modelos Moleculares , Estructura MolecularRESUMEN
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
Asunto(s)
Antivirales/química , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Hepacivirus/efectos de los fármacos , Quinolinas/química , Quinolonas/química , Tiazinas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Simulación por Computador , Cristalografía por Rayos X , ARN Polimerasas Dirigidas por ADN/metabolismo , Perros , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Quinolinas/síntesis química , Quinolinas/farmacocinética , Quinolonas/síntesis química , Quinolonas/farmacología , Ratas , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/farmacología , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Pirrolidinonas/química , Tiazinas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacocinética , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
Hepsin is an integral membrane protein that may participate in cell growth and in maintaining proper cell morphology and is overexpressed in a number of primary tumors. We have determined the 1.75 A resolution structure of the extracellular component of human hepsin. This structure includes a 255-residue trypsin-like serine protease domain and a 109-residue region that forms a novel, poorly conserved, scavenger receptor cysteine-rich (SRCR) domain. The two domains are associated with each other through a single disulfide bond and an extensive network of noncovalent interactions. The structure suggests how the extracellular region of hepsin may be positioned with respect to the plasma membrane.
Asunto(s)
Espacio Extracelular/química , Receptores Inmunológicos/química , Serina Endopeptidasas/química , Secuencia de Aminoácidos , Membrana Celular/química , Humanos , Datos de Secuencia Molecular , Conformación Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Receptores Depuradores , Alineación de SecuenciaRESUMEN
The use of fragments with low binding affinity for their targets as starting points has received much attention recently. Screening of fragment libraries has been the most common method to find attractive starting points. Herein, we describe a unique, alternative approach to generating fragment leads. A binding model was developed and a set of guidelines were then selected to use this model to design fragments, enabling our discovery of a novel fragment with high LE.
Asunto(s)
Química Farmacéutica , Diseño de Fármacos , Modelos MolecularesRESUMEN
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.