ABSTRACT
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
Subject(s)
Cholesterol, HDL/blood , PPAR alpha/agonists , Propionates/chemical synthesis , Thiazoles/chemical synthesis , Animals , Apolipoprotein A-I/genetics , Cholesterol, VLDL/blood , Crystallography, X-Ray , Dogs , Dyslipidemias/blood , Dyslipidemias/drug therapy , Humans , Ligands , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Molecular , PPAR alpha/chemistry , Propionates/pharmacokinetics , Propionates/pharmacology , Protein Structure, Tertiary , Rats , Rats, Wistar , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Triglycerides/bloodABSTRACT
The conjugate additions of Reformatsky reagents, organocuprate reagents, and hydroxylamines to a [4.3.0]-bicyclic enelactam derived from 6-oxopipecolic acid have been investigated, and found to be efficient, proceeding with excellent exo-stereocontrol, with the exception of N-benzyl-O-benzylhydroxylamine, which gives predominantly the product of endo-addition. These adducts can be readily converted to substituted piperidinones.
ABSTRACT
The synthesis and alkylation of [4.3.0]-bicyclic lactams, derived from 6-oxopipecolic acid, have been investigated. Alkylation can proceed with predominantly exo-diastereoselectivity, but the efficiency of this process depends on the substitution at the hemiaminal ether system. These products can be readily deprotected to give substituted hydroxymethyl lactams in good yield.
