RESUMO
Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/síntese química , Adamantano/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Tecido Adiposo/enzimologia , Animais , Encéfalo/enzimologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Humanos , Indicadores e Reagentes , Fígado/enzimologia , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A series of xanthine mimetics containing 5,5 and 5,6 heterocycle fused imidazoles were synthesized as dipeptidyl peptidase IV inhibitors. Compound 7 is potent (h-DPPIV K(i)=2nM) and exhibits excellent selectivity and no species specificity against rat and human enzymes. The X-ray structure confirms that the binding mode of 7 to rat DPPIV is similar to the parent xanthines.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/farmacologia , Xantinas/farmacologia , Animais , Dipeptidil Peptidase 4/química , Imidazóis/farmacologia , Cinética , Modelos Moleculares , Inibidores de Proteases/síntese química , Conformação Proteica , Ratos , Relação Estrutura-Atividade , Difração de Raios X , Xantinas/síntese químicaRESUMO
We report the discovery of a novel class of glucocorticoid receptor (GR) antagonists based on the chromene molecular scaffold. The compounds exhibit good functional potency and an improved receptor selectivity profile for GR over other steroid receptors when compared to the classical steroidal GR-antagonist, RU-486.
Assuntos
Benzopiranos/síntese química , Benzopiranos/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Benzopiranos/química , Avaliação Pré-Clínica de Medicamentos , Mifepristona/farmacologiaRESUMO
Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627, ABT-546, A-182086 and A-192621, which exhibit difference in selectivity for ET(A) and ET(B) receptors. In this report, we compare the potency and selectivity of these four antagonists in inhibiting (125)I-labelled ET-1 binding to cloned human ET(A) and ET(B) receptors, and in blocking ET-1-induced functional responses (arachidonic acid release and phosphatidylinositol hydrolysis).
Assuntos
Antagonistas dos Receptores de Endotelina , Vasodilatadores/farmacologia , Animais , Ácido Araquidônico/metabolismo , Atrasentana , Ligação Competitiva , Células CHO , Linhagem Celular , Cricetinae , Endotelina-1/metabolismo , Endotelina-1/farmacologia , Humanos , Hidrólise , Radioisótopos do Iodo/metabolismo , Fosfatidilinositóis/metabolismo , Pirrolidinas/farmacologia , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo , Sulfonamidas/farmacologia , TransfecçãoRESUMO
Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627 (atrasentan), ABT-546, A-182086 and A-192621, which exhibit differences in selectivity for ET(A) and ET(B) receptors. In this report, we compare the efficacy, potency and pharmacokinetic properties of these four antagonists, including potency in inhibiting ET-1- or Sarafotoxin 6c-induced vessel constriction in isolated arteries and efficacy in antagonizing ET-1-, big ET-1- or Sarafotoxin 6c-induced pressor responses in rats.
