1912
T.-Y. Tsai et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1908–1912
(IC50 > 20 lM). The inhibitor also exhibited excellent aqueous
stability. The in vivo effects of compound 13f, including inhibition
of plasma DPP-IV activity and suppression of blood glucose eleva-
tion, were also demonstrated. The result of these pharmacological
studies indicates that 13f is a potent, selective, and orally available
inhibitor of DPP-IV.
Acknowledgement
National Health Research Institutes, Taiwan, financially sup-
ported the study.
References and notes
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120
110
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90
80
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1
50
40
30
20
10
0
13f
Control
0
5
10
15
20
25
Time (hr)
Figure 3. DPP-IV inhibition in rats for 2 (n = 5) and 13f (n = 4) at 3 mpk po versus
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plasma DPP-IV inhibition assay,21 the compounds were adminis-
tered to Wistar rats by oral route at 3 mpk, blood samples were
collected and analyzed for plasma DPP-IV activity (Fig. 3). A max-
imum inhibition of plasma DPP-IV activity was observed approxi-
mately 30 min after the oral dosing of compounds 2 or 13f, the
inhibition was >80% from 30 min to 4 h and >60% at 8 h. The com-
pound 13f showed similar inhibition profile of plasma DPP-IV
activity as 2. The in vivo effects shown in Figures 2 and 3 demon-
strate the ability of 13f to both significantly decrease the glucose
excursion and inhibit plasma DPP-IV activity, and these pharmaco-
logical profiles of 13f are comparable to those of compound 2, a
DPP-IV inhibitor, which is a diabetes drug for the European market.
In summary, we have identified a novel series of glutamic acid
derivatives as potent and selective DPP-IV inhibitors. Notable
among these is compound 13f having 3,3-dimethyl substituents
in the b-position of the P2 site glutamic acid. This compound is
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file over DPP8 (IC50 = 14 lM), FAP (IC50 > 20 lM) and DPP-II