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Methylation of the amide nitrogen (compound 25; using
MeI and NaH) or switching back to the ether linkage
(compound 26; synthetic procedure according to
Scheme 3) resulted in a drastic reduction of activity,
whereas a ketomethylene replacement of the amide
(compound 29a) slightly improved both potency and
efficacy. Unfortunately, the depicted synthesis route to
compound 29a (Scheme 6) predominantly gave the
undesired, inactive regioisomer 29b (ratio 29a/
29b ꢀ 1:7).
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M. H.; Willson, T. M.; Oliver, W. R.; Sternbach, D. D.
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In summary, we were able to identify a novel isoxazole
scaffold displaying PPAR activity based on hits derived
from a high throughput screen. In an attempt to im-
prove the activity to a full agonist profile, we designed
and synthesized a number of analogs showing various
degrees of potency, efficacy, and selectivity for the
PPAR subtypes. Compounds 24e and 29a are potent
and highly selective activators of the PPARd receptor.
Notably this series is different from the common PPAR
agonist motifs reported in the literature. The com-
pounds do not seem to require a flexible linker between
functional head and hydrophobic tail, a unique feature
distinct from most reported PPAR modulators. The
isoxazoles presented may be used as tool compounds
for further elucidation of the specific biological roles
of PPARd.
19. Leibowitz, M. D.; Fievet, C.; Hennuyer, N.; Peinado-
Onsurbe, J.; Duez, H.; Berger, J.; Cullinan, C. A.;
Sparrow, C. P.; Baffic, J.; Berger, G. D.; Santini, C. J.;
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Y.; Sumi, K.; Iguchi, H.; Ito, S.; Doi, T.; Hamakubo,
T.; Naito, M.; Auwerx, J.; Yanagisawa, M.; Kodama,
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Acknowledgments
We gratefully acknowledge Drs. T.R. Vedananda, San-
dra Teixeira, and Peter G. Schultz for their helpful dis-
cussions and support.
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