title: Synthesis and identification of [1,2,4]thiadiazole derivatives as a new series of potent and orally active dual agonists of peroxisome proliferator-activated receptors alpha and delta.
abstract: Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome.
authors.affiliation: Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Cedarbrook Corporate Center, 8 Clarke Drive, 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: Jun 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; D016632:Apolipoprotein A-I / Q000235:genetics; D002460:Cell Line; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000819:agonists*; D047494:PPAR delta / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047494:PPAR delta; D013830:Thiadiazoles