Document Detail

Synthesis and structure-activity relationships of thiadiazole-derivatives as potent and orally active peroxisome proliferator-activated receptors alpha/delta dual agonists.
MedLine Citation:
PMID:  18155554     Owner:  NLM     Status:  MEDLINE    
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.
Lan Shen; Yan Zhang; Aihua Wang; Ellen Sieber-McMaster; Xiaoli Chen; Patricia Pelton; June Z Xu; Maria Yang; Peifang Zhu; Lubing Zhou; Michael Reuman; Zhiyong Hu; Ronald Russell; Alan C Gibbs; Hamish Ross; Keith Demarest; William V Murray; Gee-Hong Kuo
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Publication Detail:
Type:  Journal Article     Date:  2007-12-08
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  16     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-31     Completed Date:  2008-06-13     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  3321-41     Citation Subset:  IM    
Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Cedarbrook Corporate Center, 8 Clarke Dr. Cranbury, NJ 08512, USA.
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MeSH Terms
Administration, Oral
Biological Availability
Gene Expression Regulation / drug effects
Metabolic Syndrome X / drug therapy
PPAR alpha / agonists*
PPAR delta / agonists*
Thiadiazoles / chemical synthesis,  chemistry*,  pharmacokinetics,  pharmacology*
Transcriptional Activation
Reg. No./Substance:
0/PPAR alpha; 0/PPAR delta; 0/Thiadiazoles

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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