1268
C. G. Caldwell et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1265–1268
concentrations following oral dosing at 2 mg/kg were
1.0 mM. Compound 48 was also examined in an oral
glucose tolerance test. Dosing of the compound in lean
C57BL6/N mice at 3 mg/kg resulted in a 42% reduction
in the glucose excursion relative to vehicle-treated
controls.
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In summary, modification of the substituted 4-amino-
cyclohexylglycine pyrrolidide lead structure by intro-
duction of fluorine substituents on the pyrrolidine ring
has been examined. The (3S,4S)- and (3R,4R)-3,4-
difluoropyrrolidine derivatives were less active inhibi-
tors of DP-IV, but the 3,3-difluoropyrrolidine analogues
showed good potency against the enzyme. Selectivity
versus QPP for the 3,3-difluoropyrrolidine analogues
was similar to that observed for the thiazolidine deriv-
atives. Compounds derived from (S)-3-fluoropyrrolidine
showed good potency versus DP-IV, with these com-
pounds generally having slightly greater activity than
the (R)-3-fluoropyrrolidides. The (S)-3-fluoro derivative
48 was found to have good pharmacokinetic properties
and produced significant activity in an oral glucose tol-
erance test in lean mice.
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Acknowledgements
The authors would like to thank Dr. Phil Eskola, Mr.
Robert Frankshun, and Mr. Joseph Leone for large-
scale preparations of several intermediates used in this
work.
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