RESUMO
As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.
Assuntos
Agonistas Adrenérgicos/química , Agonistas de Receptores Adrenérgicos beta 3 , Receptores Adrenérgicos beta 2/química , Sulfonamidas/química , Agonistas Adrenérgicos/síntese química , Agonistas Adrenérgicos/farmacocinética , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Cães , Descoberta de Drogas , Humanos , Modelos Químicos , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
Sordarin is a unique natural product antifungal agent that is an inhibitor of elongation factor 2. To improve biological activity, we synthesized various compounds by novel modification of the aglycone, sordaricin. As a result, we have discovered the novel sordarin derivative FR290581. This compound exhibited superior activity and a good pharmacokinetic profile, and also displayed good in vivo activity against Candida albicans.