title: Inhibition of dipeptidyl peptidase IV by novel inhibitors with pyrazolidine scaffold.
abstract: 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.
authors.affiliation: 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>
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Kwang-Rok
authors.initials: KR
authors.lastname: Kim
authors.forename: Sang-Dal
authors.initials: SD
authors.lastname: Rhee
authors.forename: Sung-Don
authors.initials: SD
authors.lastname: Yang
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Park
authors.forename: Jae Mok
authors.initials: JM
authors.lastname: Lee
authors.forename: Won Hoon
authors.initials: WH
authors.lastname: Jung
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Lee
authors.forename: Hee Youn
authors.initials: HY
authors.lastname: Kim
mesh_terms: 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
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D011480:Protease Inhibitors; D011720:Pyrazoles; D018819:Dipeptidyl Peptidase 4