國家衛生研究院 NHRI:Item 3990099045/3610
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    题名: Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor
    作者: Wu, JJ;Tang, HK;Yeh, TK;Chen, CM;Shy, HS;Chu, YR;Chien, CH;Tsai, TY;Huang, YC;Huang, YL;Huang, CH;Tseng, HY;Jiaang, WT;Chao, YS;Chen, X
    贡献者: Division of Biotechnology and Pharmaceutical Research
    摘要: 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.
    日期: 2009-07-15
    關聯: Biochemical Pharmacology. 2009 Jul 15;78(2):203-210.
    Link to: http://dx.doi.org/10.1016/j.bcp.2009.03.032
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0006-2952&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000266697000012
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=65649147246
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