RESUMO
By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 µM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.
Assuntos
Amidinas/síntese química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Guanidinas/síntese química , Amidinas/química , Amidinas/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Animais , Ácido Aspártico Endopeptidases/química , Encéfalo/metabolismo , Células CHO , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Simulação por Computador , Cricetinae , Cristalografia por Raios X , Cães , Estabilidade de Medicamentos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Guanidinas/química , Guanidinas/farmacologia , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , EstereoisomerismoRESUMO
Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11beta-HSD1 (IC(50) = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC(50) = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11beta-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA(y) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.
