Benzoyl 2-methyl indoles as selective PPARgamma modulators.
Routine screening for human PPAR ligands yielded compounds 1 and 2, both of which were sub-micromolar hPPARgamma 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 PPARgamma modulators (SPPARgammaMs). SPPARgammaM 24 displayed robust anti-diabetic activity with an improved therapeutic window in comparison to a PPARgamma full agonist in a rodent efficacy model.
Acton
John J
JJ
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. john_acton@merck.com
Black
Regina M
RM
Jones
A Brian
AB
Moller
David E
DE
Colwell
Lawrence
L
Doebber
Thomas W
TW
Macnaul
Karen L
KL
Berger
Joel
J
Wood
Harold B
HB
D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism*; D008024:Ligands; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism
D001565:Benzoates; D007211:Indoles; D018836:Inflammation Mediators; D008024:Ligands; D047495:PPAR gamma