(2S,4S)-4-Fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}-pyrrolidine-2-carbonitrile monobenzenesulfonate (TS-021) is a selective and reversible dipeptidyl peptidase IV inhibitor.
The incretin hormone glucagon-like peptide-1 (GLP-1) has significant roles in the regulation of postprandial glucose metabolism, and the active form of GLP-1 is rapidly degraded by dipeptidyl peptidase (DPP)-IV. Therefore, DPP-IV inhibition is a promising approach for the treatment of type 2 diabetes. In the present study, we investigated the character of a DPP-IV inhibitor, TS-021, (2S, 4S)-4-fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}-pyrrolidine-2-carbonitrile monobenzenesulfonate both in vitro and in vivo. TS-021 inhibits DPP-IV activity in human plasma with an IC(50) value of 5.34nM. In kinetics experiments, TS-021 had a relatively higher dissociation rate constant, with a k(off) value of 1.09×10(-3)s, despite exhibiting a potent human plasma DPP-IV inhibition activity with a K(i) value of 4.96nM. TS-021 exhibited significant inhibition selectivity against DPP-8 (>600 fold), DPP-9 (>1200 fold) and other peptidases examined (>15,000 fold). In normal rats, dogs and monkeys, a single oral dose of TS-021 exhibited favorable pharmacokinetic profiles. In Zucker fatty (fa/fa) rats, a rat model of obesity and impaired glucose tolerance, the oral administration of TS-021 resulted in the suppression of plasma DPP-IV activity and an increase in the active form of GLP-1. Furthermore, TS-021 exhibited a significant improvement in glucose tolerance by increasing the plasma insulin level during oral glucose tolerance tests at doses of 0.02-0.5mg/kg. These results suggest that TS-021 is a selective and reversible dipeptidyl peptidase IV inhibitor and has excellent characteristics as an oral anti-diabetic agent for postprandial hyperglycemia in patients with impaired glucose tolerance or type 2 diabetes.
Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. atsushi.tajima@po.rd.taisho.co.jp
Atsushi
A
Tajima
Koji
K
Yamamoto
Akinori
A
Kozakai
Lisa
L
Okumura-Kitajima
Yasuo
Y
Mita
Kiyokazu
K
Kitano
Shigeji
S
Jingu
Shiro
S
Nakaike
D000284:Administration, Oral; D000818:Animals; D001557:Benzenesulfonates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test; D000882:Haplorhini; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D010446:Peptide Fragments / Q000097:blood; D011759:Pyrrolidines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity
C558997:(2S,4S)-4-Fluoro-1-(((2-hydroxy-1,1-dimethylethyl)amino)acetyl)-pyrrolidine-2-carbonitrile monobenzenesulfonate; D001557:Benzenesulfonates; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D010446:Peptide Fragments; D011759:Pyrrolidines; C055453:glucagon-like peptide 1 (7-36)amide; C032365:benzenesulfonic acid; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4