Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor.
DPP-IV (EC 3.4.14.5) is a validated drug target for human type II diabetes. DPP-IV inhibitors without DPP8/9 inhibitory activity have been sought because a possible association has been reported between a "DPP8/9 inhibitor" and severe toxicity in animals. However, at present, it is not known whether the observed toxicity is associated with DPP8/9 inhibition, or an off-target effect induced by the compound. We investigated whether the inhibition of DPP8/9 is the cause of the severe toxicity in animals using a very potent and selective DPP8/9 inhibitor with different pharmacophore, 1G244. By Ki measurement, 1G244 is 15- and 8-fold more potent against DPP8 and DPP9, respectively, than the "DPP8/9 inhibitor". Strikingly, the "DPP8/9 inhibitor" does not penetrate the plasma membrane but remains outside the cells, whereas 1G244 readily enters the cells, even at low doses. By repeatedly exposing Sprague-Dawley rats to 1G244 by intravenous injection for a period of 14 days, we observed no significant toxicological symptoms associated with 1G244. Blood and serum chemistry parameters were all within the normal ranges for the treated animals. Because of the high potency, good membrane penetration and adequate tissue distribution of 1G244, the mild symptoms observed are probably associated with DPP8/9 inhibition.
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35 Keyan Rd., Zhu Nan Town, Miaoli County 350, Taiwan, ROC.
Jia-Jing
JJ
Wu
Hung-Kuan
HK
Tang
Teng-Kuang
TK
Yeh
Chi-Min
CM
Chen
Hrong-Shing
HS
Shy
Yue-Ru
YR
Chu
Chia-Hui
CH
Chien
Ting-Yueh
TY
Tsai
Yu-Chen
YC
Huang
Yu-Lin
YL
Huang
Chih-Hsiang
CH
Huang
Huan-Yi
HY
Tseng
Weir-Torn
WT
Jiaang
Yu-Sheng
YS
Chao
Xin
X
Chen
D000818:Animals; D002460:Cell Line; D004150:Dipeptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D011480:Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D011480:Protease Inhibitors; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C487997:DPP8 protein, human