RESUMO
Antagonists of the 5-HT(6) receptor have been shown to improve cognitive function in a wide range of animal models and as such may prove to be attractive agents for the symptomatic treatment of cognitive disorders such as Alzheimer's disease (AD) and schizophrenia. We report herein the identification and SAR around N-(2-aminoalkyl)-1-(arylsulfonyl)indoline-3-carboxamides-a novel chemotype of 5-HT(6) antagonists.
Assuntos
Amidas/química , Indóis/química , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Amidas/farmacologia , Animais , Disponibilidade Biológica , Descoberta de Drogas , Humanos , Indóis/farmacologia , Masculino , Microssomos , Farmacocinética , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/química , Relação Estrutura-AtividadeRESUMO
Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.
Assuntos
Catepsina K/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Nitrilas/síntese química , Nitrilas/farmacologia , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Desenho de Fármacos , Descoberta de Drogas , Indicadores e Reagentes , Modelos Moleculares , Curva ROC , Relação Estrutura-Atividade , Torsades de Pointes/tratamento farmacológicoRESUMO
Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.