title: DA-1229, a novel and potent DPP4 inhibitor, improves insulin resistance and delays the onset of diabetes.
abstract: OBJECTIVE
  To characterize the pharmacodynamic profile of DA-1229, a novel dipeptidyl peptidase (DPP) 4 inhibitor.
  
  
  METHODS
  Enzyme inhibition assays against DPP4, DPP8 and DPP9. Antidiabetic effects of DA-1229 in HF-DIO mice and young db/db mice.
  
  
  RESULTS
  DA-1229 was shown to potently inhibit the DPP4 enzyme in human and murine soluble forms and the human membrane-bound form with IC(50) values of 0.98, 3.59 and 1.26 nM, respectively. As a reversible and competitive inhibitor, DA-1229 was more selective to human DPP4 (6000-fold) than to human DPP8 and DPP9. DA-1229 (0.1-3mg/kg) dose-dependently inhibited plasma DPP4 activity, leading to increased levels of plasma GLP-1 and insulin, and thereby lowering blood glucose levels in mice. In high fat diet-fed (HF) mice, a single oral dose of 100mg/kg of DA-1229 reduced plasma DPP4 activity by over 80% during a 24h period. Long-term treatment with DA-1229 for 8 weeks revealed significant improvements in glucose intolerance and insulin resistance, accompanied by significant body weight reduction. However, it remains unclear whether there is a direct causal relationship between DPP4 inhibition and body weight reduction. In young db/db mice, the DA-1229 treatment significantly reduced blood glucose excursions for the first 2 weeks, resulting in significantly lower levels of HbA1c at the end of the study. Furthermore, the pancreatic insulin content of the treatment group was significantly higher than that of the db/db control.
  
  
  CONCLUSIONS
  DA-1229 as a novel and selective DPP4 inhibitor improves the insulin sensitivity in HF mice and delays the onset of diabetes in young db/db mice.
authors: Dong-A Pharm. Research Center, 47-5 Sanggal-dong, Giheung-gu, Yongin-si, Gyeonggi-do, 446-905, Republic of Korea.
authors: Mi-Kyung
authors: MK
authors: Kim
authors: Yu Na
authors: YN
authors: Chae
authors: Ha Dong
authors: HD
authors: Kim
authors: Eun Kyoung
authors: EK
authors: Yang
authors: Eun Jung
authors: EJ
authors: Cho
authors: Song-hyen
authors: SH
authors: Choi
authors: Ye-Hwang
authors: YH
authors: Cheong
authors: Hae-Sun
authors: HS
authors: Kim
authors: Heung Jae
authors: HJ
authors: Kim
authors: Yeong Woo
authors: YW
authors: Jo
authors: Moon-Ho
authors: MH
authors: Son
authors: Soon-Hoe
authors: SH
authors: Kim
authors: Chang Yell
authors: CY
authors: Shin
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use*; D011897:Random Allocation; D013997:Time Factors
chemical_list: C557982:4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010879:Piperazines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4