title: Synthesis and structure-activity relationships of thiadiazole-derivatives as potent and orally active peroxisome proliferator-activated receptors alpha/delta dual agonists.
abstract: Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome.
authors.affiliation: Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Cedarbrook Corporate Center, 8 Clarke Dr. Cranbury, NJ 08512, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Shen
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Aihua
authors.initials: A
authors.lastname: Wang
authors.forename: Ellen
authors.initials: E
authors.lastname: Sieber-McMaster
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Chen
authors.forename: Patricia
authors.initials: P
authors.lastname: Pelton
authors.forename: June Z
authors.initials: JZ
authors.lastname: Xu
authors.forename: Maria
authors.initials: M
authors.lastname: Yang
authors.forename: Peifang
authors.initials: P
authors.lastname: Zhu
authors.forename: Lubing
authors.initials: L
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: Reuman
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Hu
authors.forename: Ronald
authors.initials: R
authors.lastname: Russell
authors.forename: Alan C
authors.initials: AC
authors.lastname: Gibbs
authors.forename: Hamish
authors.initials: H
authors.lastname: Ross
authors.forename: Keith
authors.initials: K
authors.lastname: Demarest
authors.forename: William V
authors.initials: WV
authors.lastname: Murray
authors.forename: Gee-Hong
authors.initials: GH
authors.lastname: Kuo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D005786:Gene Expression Regulation / Q000187:drug effects; D024821:Metabolic Syndrome / Q000188:drug therapy; D051379:Mice; D047493:PPAR alpha / Q000819:agonists*; D047494:PPAR delta / Q000819:agonists*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015533:Transcriptional Activation
chemical_list: D047493:PPAR alpha; D047494:PPAR delta; D013830:Thiadiazoles