RESUMO
A full account of studies that culminated in the total synthesis of both antipodes and the assignment of its absolute configuration of Saudin, a hypoglycemic natural product. Two approaches are described, the first proceeding though bicyclic lactone intermediates and related second monocyclic esters. The former was obtained via asymmetric Diels-Alder cycloaddition and the latter by an asymmetric annulation protocol. Both approaches employ a Lewis acid promoted Claisen rearrangement, with the successful approach taking advantage of bidentate chelation to control the facial selectivity of the key Claisen rearrangement.
RESUMO
High throughput screening of our compound collection led to the discovery of a novel series of N-alkyl-5H-pyrido[4,3-b]indol-1-amines as urotensin-II receptor antagonists. Synthesis, initial structure and activity relationships, functional and animal ortholog activities of the series are described.
Assuntos
Aminas/síntese química , Aminas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Urotensinas/antagonistas & inibidores , Aminas/química , Animais , Técnicas de Química Combinatória , Camundongos , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.
Assuntos
Metilaminas/farmacologia , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Vasoconstritores/farmacologia , Sítios de Ligação , Humanos , Metilaminas/síntese química , Modelos Químicos , Piperidinas/síntese química , Estereoisomerismo , Relação Estrutura-Atividade , Vasoconstritores/síntese químicaRESUMO
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
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
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.