Discovery of a novel class of 2-mercaptohexanoic acid derivatives as highly active PPARalpha agonists.
A novel and robust scaffold for highly active PPARalpha agonists based on the 2-mercaptohexanoic acid substructure is presented. Systematic structural variation of the substitution pattern of the phenolic backbone yielded detailed SAR especially of ortho and meta substituents. We corroborated the importance of the sulfur atom as well as of the n-butyl chain for PPARalpha activity in the 2-mercaptohexanoic acid head group by preparation of carbon analogs and alpha-unsubstituted derivatives. Compound 10 represents a low nano molar active PPARalpha activator with excellent selectivity towards PPARgamma.
Zettl
Heiko
H
Goethe-University Frankfurt, Institute of Pharmaceutical Chemistry/ZAFES/LiFF, Max-von-Laue-Str. 9, D-60348 Frankfurt/M., Germany.
Steri
Ramona
R
Lämmerhofer
Michael
M
Schubert-Zsilavecz
Manfred
M
D002208:Caproates / Q000138:chemical synthesis* / Q000494:pharmacology; D002244:Carbon / Q000737:chemistry; D002625:Chemistry, Organic / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists* / Q000737:chemistry; D019800:Phenol / Q000737:chemistry; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013455:Sulfur / Q000737:chemistry
D002208:Caproates; D047493:PPAR alpha; D013438:Sulfhydryl Compounds; D019800:Phenol; D013455:Sulfur; D002244:Carbon