RESUMO
A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.
Assuntos
Osteogênese/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Proteínas Wnt/agonistas , beta Catenina/agonistas , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/química , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos , Modelos Moleculares , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMO
Pyrrole[2,3-d]azepines have been identified as potent agonists of the farnesoid X receptor (FXR). Based on the planar X-ray crystal structure of WAY-362450 1 in the ligand binding domain and molecular modeling studies, non-planar reduced compounds were designed which led to agonists that exhibit high aqueous solubility and retain moderate in vitro potency.
Assuntos
Azepinas/farmacologia , Pirróis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Azepinas/química , Humanos , Modelos Moleculares , Ligação Proteica , Pirróis/química , Receptores Citoplasmáticos e Nucleares/química , Relação Estrutura-AtividadeRESUMO
Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.