Indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail groups, a new class of potent PPAR alpha/gamma/delta pan agonists: synthesis, structure-activity relationship, and in vivo efficacy.
Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.
Rudolph
Joachim
J
Department of Chemistry Research, Bayer HealthCare Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, Connecticut 06516, USA. joachim.rudolph.b@bayer.com
Chen
Libing
L
Majumdar
Dyuti
D
Bullock
William H
WH
Burns
Michael
M
Claus
Thomas
T
Dela Cruz
Fernando E
FE
Daly
Michelle
M
Ehrgott
Frederick J
FJ
Johnson
Jeffrey S
JS
Livingston
James N
JN
Schoenleber
Robert W
RW
Shapiro
Jeffrey
J
Yang
Ling
L
Tsutsumi
Manami
M
Ma
Xin
X
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D011869:Radioligand Assay; D051381:Rats; D011924:Rats, Zucker; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000085:Acetates; D016632:Apolipoprotein A-I; D007004:Hypoglycemic Agents; D007189:Indans; D008055:Lipids; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D014230:Triazoles