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Biochemistry, Pharmacokinetics, and Toxicology of a Potent and Selective DPP8/9 Inhibitor

Biochemistry, Pharmacokinetics, and Toxicology of a Potent and Selective DPP8/9 Inhibitor

Jia-Jing Wu, Hung-Kuan Tang, Teng-Kuang Yeh, Chi-Min Chen, Hrong-Shing Shy, Yue-Ru Chu, Chia-Hui Chien, Ting-Yueh Tsai, Yu-Chen Huang, Yu-Lin Huang, Chih-Hsiang Huang, Huan-Yi Tseng, Weir-Torn Jiaang, Yu-Sheng Chao, etc.

Biochem Pharmacol. 2009 Jul 15;78(2):203-10.

PMID: 19439267

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP847928329	1G244		847928-32-9	Price

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