RESUMO
Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.
Assuntos
Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Isoquinolinas/farmacologia , Pirrolidinonas/farmacologia , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Dipeptidases/antagonistas & inibidores , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Tolerância a Medicamentos , Inibidores Enzimáticos/síntese química , Glucose/administração & dosagem , Glucose/antagonistas & inibidores , Humanos , Técnicas In Vitro , Isoquinolinas/síntese química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Pirrolidinonas/síntese química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Fatores de TempoRESUMO
To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure-activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8.
