RESUMO
A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood.
Assuntos
Receptores CCR2/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Administração Oral , Animais , Técnicas de Introdução de Genes , Guanosina 5'-O-(3-Tiotrifosfato)/sangue , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica/efeitos dos fármacos , Ratos , Receptores CCR2/genética , Receptores CCR2/metabolismo , Albumina Sérica/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.
Assuntos
Química Farmacêutica/métodos , Piperazinas/farmacologia , Receptores Opioides kappa/antagonistas & inibidores , Taurina/análogos & derivados , Urotensinas/antagonistas & inibidores , Acamprosato , Animais , Aorta/metabolismo , Desenho de Fármacos , Humanos , Hipertensão/tratamento farmacológico , Modelos Químicos , Piperazinas/química , Ratos , Relação Estrutura-Atividade , Taurina/efeitos dos fármacosRESUMO
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
Assuntos
Química Farmacêutica/métodos , Urotensinas/antagonistas & inibidores , Administração Oral , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Diaminas/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Ratos , Receptores Opioides kappa/química , Estereoisomerismo , Relação Estrutura-Atividade , Urotensinas/químicaRESUMO
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
Assuntos
Compostos de Anilina/farmacologia , Piperidonas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Administração Oral , Compostos de Anilina/síntese química , Compostos de Anilina/química , Animais , Disponibilidade Biológica , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Peso Molecular , Piperidonas/síntese química , Piperidonas/química , Ratos , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.
Assuntos
Amidas/síntese química , Anti-Hipertensivos/síntese química , Indazóis/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridonas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Aorta/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Técnicas In Vitro , Indazóis/farmacocinética , Indazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Proteínas Serina-Treonina Quinases/química , Piridonas/farmacocinética , Piridonas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade , Quinases Associadas a rhoRESUMO
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
Assuntos
Anti-Hipertensivos/síntese química , Benzimidazóis/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Oxidiazóis/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Aorta/fisiologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Técnicas In Vitro , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade , Quinases Associadas a rhoRESUMO
Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.