RESUMO
The synthesis and structure-activity relationship of a novel series of aminopyrimidines are exemplified. Results of key compounds from within this series in the E-selectin reporter cell assay are also reported.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Selectina E/metabolismo , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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 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.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Animais , Células CHO , Fenômenos Químicos , Físico-Química , Quimiotaxia/efeitos dos fármacos , Cricetinae , Cricetulus , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Técnicas In Vitro , Cinética , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Receptores CXCR3 , Relação Estrutura-Atividade , TransfecçãoRESUMO
A novel series of aminopyrimidine IKK2 inhibitors have been developed which show excellent in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The relative potency and selectivity of these compounds has been rationalized using QSAR and structure-based modelling.
