Benzoyl 2-methyl indoles as selective PPARγ modulators

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Abstract

Routine screening for human PPAR ligands yielded compounds 1 and 2, both of which were sub-micromolar hPPARγ agonists. Synthetic modifications of these leads led to a series of potent substituted 3-benzyl-2-methyl indoles, a subset of which were noted to be selective PPARγ modulators (SPPARγMs). SPPARγM 24 displayed robust anti-diabetic activity with an improved therapeutic window in comparison to a PPARγ full agonist in a rodent efficacy model.

Graphical abstract

A series of selective PPARγ modulators (SPPARγMs) and their development from hPPARγ active screening leads 1 and 2 is described. SPPARγM 24 displayed robust anti-diabetic activity with an improved therapeutic window in comparison to a PPARγ full agonist in a rodent efficacy model.

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Acknowledgements

We are indebted to Dr. Peter Meinke for critical reading of this manuscript. We also wish to acknowledge the skills and hard work of the many scientists who provided biological support including Margaret Wu, John Ventre, Roger Meurer, Neelam Sharma, Chhabi Biswas, Raul Alvaro, and Zhesheng Chen.

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    Present address: Merck Research Laboratories, Terlings Park, United Kingdom.

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