Discovery of a novel class of 2-mercaptohexanoic acid derivatives as highly active PPARα agonists
摘要:
A novel and robust scaffold for highly active PPAR alpha 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 PPAR alpha 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 PPAR alpha activator with excellent selectivity towards PPAR gamma. (C) 2009 Elsevier Ltd. All rights reserved.
A novel and robust scaffold for highly active PPAR alpha 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 PPAR alpha 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 PPAR alpha activator with excellent selectivity towards PPAR gamma. (C) 2009 Elsevier Ltd. All rights reserved.
Identification of 2-mercaptohexanoic acids as dual inhibitors of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1
5-Lipoxygenase (5-LO) and microsomal prostaglandinE2 synthase (mPGES)-1 are key enzymes in the biosynthesis of leukotrienes and prostaglandin (PG)E2, respectively, and are considered as valuable targets for the treatment of inflammatory diseases. Here, we present the identification of 2-mercaptohexanoic acid derivatives as dual inhibitors of 5-LO and mPGES-1. The lead compound 2(4-(3-biphenyloxyp