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Submitted on January 10, 2005
Accepted on April 5, 2005
/
Dual Agonist with a Unique In Vitro Profile and Potent Glucose and Lipid Effects in Rodent Models of Type 2 Diabetes and Dyslipidemia
Endocrinology Division, Lilly Research Laboratories, Indianapolis, IN; Lead Optimization Biology, Lilly Research Laboratories, Indianapolis, IN; Cardiovascular Research, Lilly Research Laboratories, Indianapolis, IN; Ligand Pharmaceuticals, San Diego, CA; Medicinal and Developmental Chemistry, Lilly Research Laboratories, Indianapolis, IN
* To whom correspondence should be addressed. E-mail: a.r.miller{at}lilly.com.
LSN862 is a novel PPAR
/
dual agonist with a unique in vitro profile that shows improvements on glucose and lipid levels in rodent models of type 2 diabetes and dyslipidemia. Data from in vitro binding, co-transfection, and co-factor recruitment assays characterize LSN862 as a high affinity PPAR partial agonist with relatively less but significant PPAR agonist activity. Using these same assays, rosiglitazone was characterized as a high affinity PPAR full agonist with no PPAR activity. When administered to Zucker Diabetic Fatty (ZDF) rats, LSN862 displayed significant glucose and triglyceride lowering and a significantly greater increase in adiponectin levels compared with rosiglitazone. Expression of genes involved in metabolic pathways in the liver and in two fat depots from compound-treated ZDF rats was evaluated. Only LSN862 significantly elevated mRNA levels of PDK-4 and bi-functional enzyme in the liver and lipoprotein lipase in both fat depots. In contrast, both LSN862 and rosiglitazone decreased PEPCK in the liver and increased malic enzyme mRNA levels in the fat. In addition, LSN862 was examined in a second rodent model of type 2 diabetes, db/db mice. In this study, LSN862 demonstrated statistically better anti-diabetic efficacy compared with rosiglitazone with an equivalent side effect profile. LSN862, rosiglitazone, and fenofibrate were each evaluated in the humanized apoA1 transgenic mouse. At the highest dose administered, LSN862 and fenofibrate reduced VLDL-C; whereas, rosiglitazone increased VLDL-C. LSN862, fenofibrate, and rosiglitazone produced maximal increases in HDL-C of 65, 54, and 30%, respectively. These findings show that PPAR full agonist activity is not necessary to achieve potent and efficacious insulin sensitizing benefits and demonstrate the therapeutic advantages of a PPAR/ dual agonist.
/ dual agonist •
PPAR partial agonist •
HDL-C •
VLDL-C •
Type 2 diabetes •
dyslipidemia
NURSA Molecule Pages Link:
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