Inhibition of dipeptidyl peptidase IV by novel inhibitors with pyrazolidine scaffold.
Inhibition of dipeptidyl peptidase IV (DPP-IV) activity has been reported to improve nutrient-stimulated insulin secretion through the stabilization of glucagon-like peptide (GLP-1). In the present study, we identified novel DPP-IV inhibitors of pyrazolidine derivatives (Compounds 1 and 2) and characterized their biological effects in vitro and in vivo. Compound 1, an isoleucine pyrazolidide with a phenyl urea group, inhibited rat plasma DPP-IV, porcine kidney DPP-IV, as well as human Caco-2 DPP-IV with IC(50) values of 1.70, 2.26, and 2.02 microM, respectively. Because of the poor pharmacokinetic properties of Compound 1, further optimization was carried out, leading to the discovery of Compound 2, which had similar in vitro activities. Compound 2 acted as a selective and competitive inhibitor of DPP-IV. MALDI-TOF mass spectrometric analysis proved that the compound (20 microM) effectively blocked the degradation of active GLP-1 peptide by 61%. Although similar in in vitro potency, marked improvement of in vivo efficacy and pharmacokinetic properties was seen with Compound 2. Oral administration of Compound 2 resulted in potent and rapid inhibition of circulating DPP-IV in C57BL/6J mice, with ED(50) values of 26mg/kg (s.c.) and 42mg/kg (p.o.). In addition, this compound improved glucose tolerance in ob/ob mice, as determined by an oral glucose tolerance test (OGTT). These results indicate that Compound 2 is a potent and selective DPP-IV inhibitor with oral anti-hyperglycemic activity in vivo.
Cheon
Hyae Gyeong
HG
Medicinal Science Division, Korea Research Institute of Chemical Technology, Jang-Dong 100, Yusung-Gu, TaeJon 305-343, South Korea. hgcheon@krict.re.kr <hgcheon@krict.re.kr>
Kim
Sung-Soo
SS
Kim
Kwang-Rok
KR
Rhee
Sang-Dal
SD
Yang
Sung-Don
SD
Ahn
Jin Hee
JH
Park
Sung-Dae
SD
Lee
Jae Mok
JM
Jung
Won Hoon
WH
Lee
Hye Sook
HS
Kim
Hee Youn
HY
D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D007004:Hypoglycemic Agents; D007328:Insulin; D011480:Protease Inhibitors; D011720:Pyrazoles; D018819:Dipeptidyl Peptidase 4