title: A novel selective peroxisome proliferator-activator receptor-gamma modulator-SPPARgammaM5 improves insulin sensitivity with diminished adverse cardiovascular effects.
abstract: The use of the thiazolidinedione insulin sensitizers rosiglitazone and pioglitazone for the treatment of type 2 diabetes mellitus in recent years has proven to be effective in helping patients resume normal glycemic control. However, their use is often associated with undesirable side effects including peripheral edema, congestive heart failure and weight gain. Here, we report the identification and characterization of a novel selective PPARgamma modulator, SPPARgammaM5 ((2S)-2-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl} phenoxy)propionic acid), which has notable insulin sensitizing properties and a superior tolerability profile to that of rosiglitazone. SPPARgammaM5 is a potent ligand of human PPARgamma with high selectivity versus PPARalpha or PPARdelta in receptor competitive binding assays. In cell-based transcriptional activation assays, SPPARgammaM5 was a potent partial agonist of human PPARgamma in comparison to the PPARgamma full agonist rosiglitazone. Compared to rosiglitazone or the PPARgamma full agonist COOH (2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid), SPPARgammaM5 induced an attenuated PPARgamma-regulated gene expression profile in fully differentiated 3T3-L1 adipocytes and white adipose tissue of chronically treated db/db mice. SPPARgammaM5 treatment also reduced the insulin resistance index by homeostasis model assessment (HOMA), suggesting an improvement in insulin resistance in these db/db mice. Treatment of obese Zucker rats with either rosiglitazone or SPPARgammaM5 resulted in an improvement in selected parameters that serve as surrogate indicators of insulin resistance and hyperlipidemia. However, unlike rosiglitazone, SPPARgammaM5 did not cause significant fluid retention or cardiac hypertrophy in these rats. Thus, compounds such as SPPARgammaM5 may offer beneficial effects on glycemic control with significantly attenuated adverse effects.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA. robert_chang@merck.com
authors.forename: Ching H
authors.initials: CH
authors.lastname: Chang
authors.forename: Lesley A
authors.initials: LA
authors.lastname: McNamara
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Wu
authors.forename: Eric S
authors.initials: ES
authors.lastname: Muise
authors.forename: Yejun
authors.initials: Y
authors.lastname: Tan
authors.forename: Harold B
authors.initials: HB
authors.lastname: Wood
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.forename: Tom W
authors.initials: TW
authors.lastname: Doebber
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCann
mesh_terms: D041721:3T3-L1 Cells; D000085:Acetates / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D002522:Chlorocebus aethiops; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006438:Hemodilution; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D047493:PPAR alpha / Q000187:drug effects / Q000378:metabolism; D047494:PPAR delta / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011422:Propionates / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014882:Water-Electrolyte Balance / Q000187:drug effects
chemical_list: C483845:2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid; C529891:2-(2-chloro-5-((3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl)methyl)phenoxy)propionic acid; D000085:Acetates; D007004:Hypoglycemic Agents; D007211:Indoles; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D011422:Propionates; D045162:Thiazolidinediones; D000077154:Rosiglitazone