RESUMO
The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Descoberta de Drogas , Metilaminas/síntese química , Metilaminas/farmacocinética , Adamantano/análogos & derivados , Adamantano/química , Adamantano/farmacologia , Administração Oral , Animais , Células CACO-2 , Cristalografia por Raios X , Ciclização , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Metilaminas/química , Metilaminas/farmacologia , Estrutura Molecular , Nitrilas/química , Nitrilas/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Fosfato de Sitagliptina , Triazóis/química , Triazóis/farmacologia , VildagliptinaRESUMO
Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.