Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8.
DPP8 is a prolyl dipeptidase homologous to DPP-IV, which is a drug target for Type II diabetes. The biological function of DPP8 is not known. To identify potent and selective chemical compounds against DPP8, we have synthesized a series of isoquinoline and isoindoline derivatives and have tested their inhibitory activity against DPP8, DPP-IV and DPP-II. Isoindoline derivatives were found to be more potent DPP8 inhibitors than isoquinoline derivatives. Isoindoline with a 1-(4,4'-difluor-benzhydryl)-piperazine group at the P2 site was observed to be a very potent DPP8 inhibitor, having an IC(50) value of 14nM with at least a 2500-fold selectivity over either DPP-IV or DPP-II. From SAR results, we speculate that the S1 site of DPP8 may be larger than that of DPP-IV, which would allow the accommodation of larger C-terminal residues, such as isoquinoline or isoindoline.
Jiaang
Weir-Torn
WT
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 161, Sec. 6, Minchiuan E. Rd., Neihu, Taipei 114, Taiwan, ROC. wtjiaang@nhri.org.tw
Chen
Yuan-Shou
YS
Hsu
Tsu
T
Wu
Ssu-Hui
SH
Chien
Chia-Hui
CH
Chang
Chung-Nien
CN
Chang
Sheng-Ping
SP
Lee
Shiow-Ju
SJ
Chen
Xin
X
D001665:Binding Sites; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; C057812:indoline; D004150:Dipeptidases; C487997:DPP8 protein, human