title: Discovery of (2R)-2-(3-{3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic acid (MK-0533): a novel selective peroxisome proliferator-activated receptor gamma modulator for the treatment of type 2 diabetes mellitus with a reduced potential to increase plasma and extracellular fluid volume.
abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are used to treat type 2 diabetes mellitus (T2DM). Widespread use of PPARgamma agonists has been prevented due to adverse effects including weight gain, edema, and increased risk of congestive heart failure. Selective PPARgamma modulators (SPPARgammaMs) have been identified that have antidiabetic efficacy and reduced toxicity in preclinical species. In comparison with PPARgamma full agonists, SPPARgammaM 6 (MK0533) displayed diminished maximal activity (partial agonism) in cell-based transcription activation assays and attenuated gene signatures in adipose tissue. Compound 6 exhibited comparable efficacy to rosiglitazone and pioglitazone in vivo. However, with regard to the induction of untoward events, 6 displayed no cardiac hypertrophy, attenuated increases in brown adipose tissue, minimal increases in plasma volume, and no increases in extracellular fluid volume in vivo. Further investigation of 6 is warranted to determine if the improvement in mechanism-based side effects observed in preclinical species will be recapitulated in humans.
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., RY800-C114, Rahway, New Jersey 07065, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Acton
authors.forename: Taro E
authors.initials: TE
authors.lastname: Akiyama
authors.forename: Ching H
authors.initials: CH
authors.lastname: Chang
authors.forename: Lawrence
authors.initials: L
authors.lastname: Colwell
authors.forename: Sheryl
authors.initials: S
authors.lastname: Debenham
authors.forename: Thomas
authors.initials: T
authors.lastname: Doebber
authors.forename: Monica
authors.initials: M
authors.lastname: Einstein
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCann
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.forename: Eric S
authors.initials: ES
authors.lastname: Muise
authors.forename: Yejun
authors.initials: Y
authors.lastname: Tan
authors.forename: Yugen
authors.initials: Y
authors.lastname: Tan
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.forename: Kenny K
authors.initials: KK
authors.lastname: Wong
authors.forename: Margaret
authors.initials: M
authors.lastname: Wu
authors.forename: Libo
authors.initials: L
authors.lastname: Xu
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Harold B
authors.initials: HB
authors.lastname: Wood
mesh_terms: D000818:Animals; D001810:Blood Volume / Q000187:drug effects; D001826:Body Fluids / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D051381:Rats; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones
chemical_list: D007004:Hypoglycemic Agents; D007211:Indoles; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077205:Pioglitazone