K579, a slow-binding inhibitor of dipeptidyl peptidase IV, is a long-acting hypoglycemic agent.
Dipeptidyl peptidase IV inhibitors are expected to be categorized in a new type of antidiabetic drugs. We had developed a long-acting dipeptidyl peptidase IV inhibitor, K579 [(S)-1-[4-methyl-1-(2-pyrimidinyl)-4-piperidylamino]acetyl-2-pyrrolidinecarbonitrile]. The aim of present study was to characterize the pharmacological profiles of K579. In normal rats, K579 suppressed the blood glucose elevation after an oral glucose tolerance test with the increment of plasma insulin and active forms of glucagon-like peptide-1 (GLP-1). During repetitive glucose loading using Zucker fatty rats, pretreatment with K579 attenuated the glucose excursion after the second glucose loading as well as the first glucose loading without inducing hypoglycemia. The kinetic study using cell extract revealed that K579 was a more potent and slower binding inhibitor than the existing dipeptidyl peptidase IV inhibitor (NVP-DPP728, 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine). These profiles of K579 might be advantageous over the existing dipeptidyl peptidase IV inhibitor with respect to less dosing frequency.
Takasaki
Kotaro
K
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co, Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka-ken, 411-8731, Japan. kotaro.takasaki@kyowa.co.jp
Iwase
Miho
M
Nakajima
Takao
T
Ueno
Kimihisa
K
Nomoto
Yuji
Y
Nakanishi
Satoshi
S
Higo
Katsuya
K
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007700:Kinetics; D008297:Male; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011485:Protein Binding; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D013997:Time Factors
C494668:(S)-1-(4-methyl-1-(2-pyrimidinyl)-4-piperidylamino)acetyl-2-pyrrolidinecarbonitrile; C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4