RESUMO
Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Modelos Moleculares , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de AcetilRESUMO
The synthesis and biological evaluation of a novel series of 2-aminoquinoline substituted piperidines and tropanes incorporating a homotropene moiety is herein described. The series exhibits potent antagonism of the CXCR3 receptor and superior physicochemical properties. Compound 24d was found to be orally bioavailable, and PK/PD studies suggested it as a suitable tool for studying the role of CXCR3 in models of disease.
Assuntos
Quinolinas/farmacologia , Receptores CXCR3/antagonistas & inibidores , Animais , Área Sob a Curva , Disponibilidade Biológica , Camundongos , Camundongos Endogâmicos BALB C , Quinolinas/química , Quinolinas/farmacocinéticaRESUMO
The optimization of a series of 1-aryl-3-piperidinyl urea derivatives is described in which incorporation of tropenyl and homotropenyl moieties has led to significant improvements in activity and drug-like properties. Replacement of the central piperidine with an exo-tropanyl unit led to the identification of compound 15 which provides a combination of excellent potency against human and murine receptors, drug-like properties and pharmacokinetics, thus providing a valuable tool for the evaluation of CXCR3 antagonists in models of human disease.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptores CXCR3/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Cicloparafinas/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Piperidinas/farmacocinética , Ureia/química , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
Development of a lead series of piperidinylurea CXCR3 antagonists has led to the identification of molecules with alternative linkages which retain good potency. A novel 5-(piperidin-4-yl)amino-1,2,4-thiadiazole derivative was found to have satisfactory in vitro metabolic stability and to be orally bioavailable in mice, giving high plasma concentrations and a half life of 5.4h.
Assuntos
Azóis/síntese química , Azóis/farmacologia , Piperidinas/química , Receptores CXCR3/antagonistas & inibidores , Aminação , Animais , Azóis/química , Células CHO , Cricetinae , Cricetulus , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Receptores CXCR3/metabolismo , Relação Estrutura-Atividade , Água/químicaRESUMO
The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Modelos Químicos , Relação Estrutura-AtividadeRESUMO
The synthesis and biological evaluation of a series of 1-aryl-3-piperidin-4-yl-urea derivatives as small-molecule CXCR3 antagonists is described. SAR studies resulted in significant improvement of potency and physicochemical properties and established the key pharmacophore of the series, and led to the identification of 9t, which exhibits an IC50 of 16 nM in the GTPgammaS35 functional assay.
