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rats and the results from this study are presented in
Figure 2 and Table 3. In rats, (R)-17c demonstrated
clearance of 133 mL/kg/min and 66% oral bioavailabili-
ty. The plasma half life of (R)-17c was 5.0 h and the
compound showed very high brain penetration, which
increased from nearly 10-fold at one hour to 25-fold at
4 h.
In summary, we have described the design and synthesis
of a novel class of potent MCH1R antagonists which
demonstrate very good oral bioavailability and other
pharmacokinetic parameters in rats. The remarkably
high brain penetration of these compounds makes them
useful tools in the study of centrally acting anorectic
agents operating through the MCH1R mechanism.
Acknowledgments
The authors thank John Saunders, Paul Conlon, and
Rich Maki for helpful discussions concerning the dis-
covery of these compounds and the preparation of the
manuscript.
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