ABSTRACT
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.
Subject(s)
Dipeptidyl Peptidase 4/drug effects , Enzyme Inhibitors/pharmacology , Isoquinolines/pharmacology , Pyrrolidinones/pharmacology , Administration, Oral , Animals , Blood Glucose/drug effects , Dipeptidases/antagonists & inhibitors , Dipeptidyl Peptidase 4/blood , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Drug Evaluation, Preclinical , Drug Tolerance , Enzyme Inhibitors/chemical synthesis , Glucose/administration & dosage , Glucose/antagonists & inhibitors , Humans , In Vitro Techniques , Isoquinolines/chemical synthesis , Male , Mice , Mice, Inbred BALB C , Molecular Conformation , Pyrrolidinones/chemical synthesis , Rats , Rats, Wistar , Structure-Activity Relationship , Time FactorsABSTRACT
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.
