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.
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.
Shen
Lan
L
Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Cedarbrook Corporate Center, 8 Clarke Drive, Cranbury, NJ 08512, USA.
Zhang
Yan
Y
Wang
Aihua
A
Sieber-McMaster
Ellen
E
Chen
Xiaoli
X
Pelton
Patricia
P
Xu
Jun Z
JZ
Yang
Maria
M
Zhu
Peifang
P
Zhou
Lubing
L
Reuman
Michael
M
Hu
Zhiyong
Z
Russell
Ronald
R
Gibbs
Alan C
AC
Ross
Hamish
H
Demarest
Keith
K
Murray
William V
WV
Kuo
Gee-Hong
GH
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
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047494:PPAR delta; D013830:Thiadiazoles