Assuntos
Diabetes Mellitus Tipo 2/terapia , Pé Diabético/terapia , Terapia a Laser/métodos , Cicatrização , Idoso , Doença Crônica , Diabetes Mellitus Tipo 2/fisiopatologia , Pé Diabético/fisiopatologia , Feminino , Seguimentos , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoAssuntos
Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/farmacologia , Peptídeo Hidrolases/metabolismo , Peptídeos Cíclicos/farmacologia , Calicreína Plasmática/antagonistas & inibidores , Animais , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/isolamento & purificação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Camundongos , Modelos Moleculares , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Calicreína Plasmática/metabolismo , Relação Estrutura-AtividadeRESUMO
AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.