[(S)-gamma-(Arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors.
Dipeptidyl peptidase-IV (DPP-IV) inhibitors, or glucagon-like peptide-1 (GLP-1) enhancers, are looked to as a potential new class of antidiabetic agents. In particular, potent and long-acting inhibitors might offer advantages in exploiting DPP-IV inhibition. The series of [(S)-gamma-(arylamino)prolyl]-(S)-2-cyanopyrrolidine compounds on which we reported previously has a highly potent inhibitory activity but seemed to be unstable in neutral aqueous solution. Here, we describe [(S)-gamma-(arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors. They are the thiazolidine analogs of [(S)-gamma-(arylamino)prolyl]-(S)-2-cyanopyrrolidine but with the electrophilic nitrile removed to improve chemical stability in aqueous solution. Of the compounds investigated in the present study, the [((S)-gamma-3,4-dicyanophenylamino)prolyl]thiazolidine 12 m was the most potent. The structure-activity relationship (SAR) of the gamma-substituent in the proline moiety of the thiazolidide was similar to that obtained with the (S)-2-cyanopyrrolidide. The gamma-substituent in the proline moiety of both the (S)-2-cyanopyrrolidide and the thiazolidide may engage with the S(2) binding pocket of DPP-IV and thereby achieve hydrophobic interaction in the same manner. Based on pharmacokinetic experiments in rats, the representative compound 11, which displayed high oral bioavailability (BA=83.9%) and long half-life in plasma (t(1/2)=5.27 h), was found to have an excellent pharmacokinetic profile.
Sakashita
Hiroshi
H
Research Laboratory II, Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
Akahoshi
Fumihiko
F
Kitajima
Hiroshi
H
Tsutsumiuchi
Reiko
R
Hayashi
Yoshiharu
Y
D000284:Administration, Oral; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008968:Molecular Conformation; D009570:Nitriles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D009570:Nitriles; D011758:Pyrroles; D013844:Thiazoles; D018819:Dipeptidyl Peptidase 4