N. Omori et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2020–2023
2023
Table 4
Rat PK profile of 10 and 12 upon iv 0.5 mg/kg and oral 1 mg/kg dosage
Compounds
Cltot (ml/mim/kg)
Cmax
(l
g/ml)
AUC(0-1)
(lg h/ml)
Vdss (l/kg)
BA (%)
B/P
CSF (nM)
fu (%)
10
12
66
33
0.006
0.026
0.04
0.26
2.62
1.74
16
52
2.63
0.64
8.8
15.9
3.8
7.1
Acknowledgments
The authors thank Kyoko Kadono, Tohru Mizutare, and Shige-
nori Yagi for conducting measurements on CYP3A4 inactivations,
rat microsomal stabilities and solubilities, respectively.
References and notes
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Figure 3. The effect of repeated administration of 12 on body weight gain in diet-
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Inhibitory effect of 12 on food intake induced by icv administra-
tion of NPY Y5 agonist ([cPP1–7, NPY19–23, Ala31, Aib32, Gln34]-
human pancreatic polypeptide) was evaluated. As shown in Fig-
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25 mg/kg oral dosing. Based on these results, the effect of 12 on
body weight gain in diet-induced obese (DIO) mice was further
evaluated, and the results are summarized in Figure 3. Although
not statistically significant, repeated administration of 12 to DIO
mice showed a tendency towards suppression of body weight gain
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21. Exploratory study from benzimidazole
manuscript.
2 will be reported in separate
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inhibition was compared to that without pre-incubation. Compound 11 gave
46% TDI with no significant effect on 12 implying the existence of a different
metabolic pathway involving a methyl substituent.26
In summary, this hit to lead study identified a novel NPY Y5
antagonist which showed significant reduction of food intake in-
duced by the NPY Y5 agonist. Further optimization efforts to im-
prove reduction of body weight gain will be reported in due course.
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