Design and synthesis of potent and subtype-selective PPARalpha agonists.

Beginning with a moderately potent PPARgamma agonist 9, a series of potent and highly subtype-selective PPARalpha agonists was identified through a systematic SAR study. Based on the results of the efficacy studies in the hamster and dog models of dyslipidemia and the desired pharmacokinetic data, the optimized compound 39 was selected for further profiling.

Steroidal and triterpenoidal fungal metabolites as ligands of liver X receptors.

Cholesterol homeostasis is tightly controlled process that involves a variety of regulators including liver X receptors (LXR). Agonists of LXR are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of microbial extracts using a LXR-scintillation proximity assay (SPA) binding assay and bioassay-guided fractionation of a number of fungal extracts led to the isolation of five ergostane and a cycloartane derivative.

Anthrabenzoxocinones from Streptomyces sp. as liver X receptor ligands and antibacterial agents.

Liver X receptors (LXR) are nuclear hormone receptors that play a critical role in cholesterol homeostasis. They regulate the expression of the ABCA1 gene, which mediates the efflux of cholesterol out of cells. LXR agonists are expected to increase cholesterol efflux, lower LDL, and raise HDL levels.

Design, synthesis, and structure-activity relationship of podocarpic acid amides as liver X receptor agonists for potential treatment of atherosclerosis.

A series of podocarpic acid amides were identified as potent agonists for Liver X receptor alpha and beta subtypes, which are members of a nuclear hormone receptor superfamily that are involved in the regulation of a variety of metabolic pathways including cholesterol metabolism. We recently reported podocarpic acid anhydride and imide dimers as potent LXR agonists. Through parallel organic synthesis, we rapidly identified a series of new podocarpate leads with stable structures exemplified by adamantyl- and phenylcyclohexylmethyl-podocarpic acid amides (14 and 18).

Diterpenoid, steroid, and triterpenoid agonists of liver X receptors from diversified terrestrial plants and marine sources.

It has been demonstrated that liver X receptors (LXR) play a significant role in cholesterol homeostasis. Agonists of LXR are expected to increase cellular cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of plant extracts using a LXR-SPA binding assay and bioassay-guided fractionation of a number of plant and marine gorgonian extracts led to the isolation of a number of active compounds.

Novel 2,3-dihydrobenzofuran-2-carboxylic acids: highly potent and subtype-selective PPARalpha agonists with potent hypolipidemic activity.

The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.

Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity.

The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems.

(2R)-2-methylchromane-2-carboxylic acids: discovery of selective PPARalpha agonists as hypolipidemic agents.

A SAR study was conducted on chromane-2-carboxylic acid toward selective PPARalpha agonisim. As a result, highly potent, and selective PPARalpha agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models.

Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters.

Liver X receptors are nuclear receptors that regulate metabolism of cholesterol. They are activated by oxysterols resulting in increased transcription of the ABCA1 gene, promoting cholesterol efflux and HDL formation. We have identified podocarpic acid anhydride as a 1nM agonist of LXRalpha and beta receptors.

Selective PPARgamma modulators with improved pharmacological profiles.

A series of metabolically robust N-benzyl-indole selective PPARgamma modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARgammaMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARgamma full agonists.

Guttiferone I, a new prenylated benzophenone from Garcinia humilis as a liver X receptor ligand.

Liver X receptors (LXR) have been implicated in cholesterol homeostasis. Agonists of LXR are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of plant extracts using a LXR-SPA binding assay and bioassay-guided fractionation of the bark and stem extract of Garcinia humilis led to the discovery of a new polyisoprenylated benzophenone named guttiferone I (1).

Discovery of a novel series of peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes and dyslipidemia.

A series of 2-aryloxy-2-methyl-propionic acid compounds and related analogues were designed, synthesized, and evaluated for their PPAR agonist activities. 2-[(5,7-Dipropyl-3-trifluoromethyl)-benzisoxazol-6-yloxy]-2-methylpropionic acid (4) was identified as a PPARalpha/gamma dual agonist with relative PPARalpha selectivity and demonstrated potent efficacy in lowering both glucose and lipids in animal models without causing body weight gain. The PPARalpha activity of 4 appeared to have played a significant role in lowering glucose levels in db/db mice.

Benzoyl 2-methyl indoles as selective PPARgamma modulators.

Routine screening for human PPAR ligands yielded compounds 1 and 2, both of which were sub-micromolar hPPARgamma agonists. Synthetic modifications of these leads led to a series of potent substituted 3-benzyl-2-methyl indoles, a subset of which were noted to be selective PPARgamma modulators (SPPARgammaMs). SPPARgammaM 24 displayed robust anti-diabetic activity with an improved therapeutic window in comparison to a PPARgamma full agonist in a rodent efficacy model.

(2R)-2-ethylchromane-2-carboxylic acids: discovery of novel PPARalpha/gamma dual agonists as antihyperglycemic and hypolipidemic agents.

A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist.

A novel peroxisome proliferator-activated receptor alpha/gamma dual agonist demonstrates favorable effects on lipid homeostasis.

Patients with type 2 diabetes mellitus exhibit hyperglycemia and dyslipidemia as well as a markedly increased incidence of atherosclerotic cardiovascular disease. Here we report the characterization of a novel arylthiazolidinedione capable of lowering both glucose and lipid levels in animal models. This compound, designated TZD18, is a potent agonist with dual human peroxisome proliferator-activated receptor (PPAR)-alpha/gamma activities.

Aryloxazolidinediones: identification of potent orally active PPAR dual alpha/gamma agonists.

A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual alpha/gamma agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.

O-arylmandelic acids as highly selective human PPAR alpha/gamma agonists.

A new class of O-arylmandelic acid PPAR agonists show excellent anti-hyperglycemic efficacy in a db/db mouse model of DM2. These PPARalpha-weighted agonists do not show the typical PPARgamma associated side effects of BAT proliferation and cardiac hypertrophy in a rat tolerability assay.

5-aryl thiazolidine-2,4-diones: discovery of PPAR dual alpha/gamma agonists as antidiabetic agents.

A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARalpha/gamma agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.

5-Aryl thiazolidine-2,4-diones as selective PPARgamma agonists.

A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.

Phenylacetic acid derivatives as hPPAR agonists.

Beginning with the weakly active lead structure 1, a new series of hPPAR agonists was developed. In vivo glucose and triglyceride lowering activity was obtained by homologation and oxamination to 3, then conversion to substituted benzisoxazoles 4 and 5. Further manipulation afforded benzofurans 6 and 7.

Amphipathic 3-phenyl-7-propylbenzisoxazoles; human pPaR gamma, delta and alpha agonists.

A series of amphipathic 3-phenylbenzisoxazoles were found to be potent agonists of human PPARalpha, gamma and delta. The optimization of acid proximal structure for in vitro and in vivo potency is described. Results of po dosed efficacy studies in the db/db mouse model of type 2 diabetes showed efficacy equal or superior to Rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase.

Increased levels of triglyceride-rich lipoproteins provoke lipid accumulation in the artery wall, triggering early inflammatory responses central to atherosclerosis like endothelial adhesion molecule expression. The endogenous mechanisms limiting such reactions remain poorly defined. Lipoprotein lipase (LPL) plays a central role in lipid metabolism by hydrolyzing triglyceride rich lipoproteins and releasing fatty acids.

Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator.

Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs.

PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion.

This study sought to determine whether the adipose depot-specific (subcutaneous [SF] vs. visceral [VF]) action of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists on fat deposition extends to the expression of lipoprotein lipase (LPL) and other key adipose lipid metabolism genes, and whether changes in LPL impact triglyceridemia. Rats were fed a standard diet or an obesity-promoting diet for 3 weeks, with or without treatment with COOH, a nonthiazolidinedione PPAR-gamma agonist.

A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a).

The liver X receptors, LXRalpha and LXRbeta, are members of the nuclear receptor superfamily. Originally identified as orphans, both receptor subtypes have since been shown to be activated by naturally occurring oxysterols. LXRalpha knockout mice fail to regulate cyp7a mRNA levels upon cholesterol feeding, implicating the role of this receptor in cholesterol homeostasis.