Pharmacological profile of a novel, non-TZD PPARgamma agonist.
OBJECTIVE
The purpose of this study was to characterize a novel, non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR)gamma agonist, RWJ-348260, via both in vitro and in vivo approaches.


METHODS
The in vitro PPARgamma activities of RWJ-348260 were assessed in PPARgamma-GAL4 co-transfection assay, PPARgamma receptor binding assay, aP2 gene induction assay and preadipocyte differentiation assay. The in vivo efficacy of the compound was determined in rodent genetic diabetes models [ob/ob mouse, db/db mouse and Zucker diabetic fatty (ZDF) rat] following multiple days of oral administration.


RESULTS
RWJ-348260 selectively activated PPARgammain vitro. In vivo, RWJ-348260 produced significant decreases in plasma glucose, HbA1c, insulin and triglyceride levels. RWJ-348260 also dose-dependently improved oral glucose tolerance. In db/db mice, the compound up-regulated PPARgamma target genes in white adipose tissues. RWJ-348260 produced a lower extent of hepatocyte lipid deposition and a smaller increase in liver weight compared to rosiglitazone in db/db mice. While RWJ-348260 effectively normalized hyperglycaemia and dyslipidaemia, it did not change haematocrit, transaminase, alkaline phosphatase, total bilirubin levels or liver weights in ZDF rats.


CONCLUSIONS
RWJ-348260 is a potent PPARgamma agonist with efficacious antidiabetic activity in diabetic animal models. The compound has an improved side-effect profile compared to rosiglitazone.
Chen
X
X
Endocrine Therapeutics and Metabolic Disorders Team, Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ 08669, USA. xchen2@prdus.jnj.com
Osborne
M C
MC
Rybczynski
P J
PJ
Zeck
R
R
Yang
M
M
Xu
J
J
Zhou
L
L
Cryan
E
E
Tang
Y
Y
Demarest
K T
KT
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006442:Glycated Hemoglobin / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy; D015228:Hypertriglyceridemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008820:Mice, Obese; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism; D015533:Transcriptional Activation; D014280:Triglycerides / Q000097:blood
D048588:Benzoxazines; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D014280:Triglycerides; C507966:RWJ 348260