RESUMO
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.
Assuntos
Química Farmacêutica , Desenho de Fármacos , Modelos MolecularesRESUMO
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.
Assuntos
Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , RatosRESUMO
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.
Assuntos
Descoberta de Drogas/métodos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Piridonas/farmacologia , Piridonas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Administração Oral , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Linhagem Celular , Ensaios Clínicos como Assunto , Humanos , Proteína Quinase 14 Ativada por Mitógeno/química , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Piridonas/administração & dosagem , Piridonas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
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.
Assuntos
Proteína Quinase 9 Ativada por Mitógeno/química , Proteínas Quinases Ativadas por Mitógeno/química , Naftalenos/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Cristalografia por Raios X , Desenho de Fármacos , Modelos Moleculares , Estrutura MolecularRESUMO
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.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Pirrolidinonas/química , Tiazinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Pirrolidinonas/síntese química , Pirrolidinonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
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.
Assuntos
Antivirais/química , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/química , Hepacivirus/efeitos dos fármacos , Quinolinas/química , Quinolonas/química , Tiazinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Simulação por Computador , Cristalografia por Raios X , RNA Polimerases Dirigidas por DNA/metabolismo , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Quinolinas/síntese química , Quinolinas/farmacocinética , Quinolonas/síntese química , Quinolonas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/farmacologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
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.