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Abundant evidence exists indicating that adipose tissue indeed serves as the primary target for the insulin-sensitizing effects of PPARg agonists whose action alters the regulation of genes involved in lipid uptake, metabolism and synthesis. PPARg agonism promotes adipocyte differentiation and its activation causes adipocyte lipid accumulation (the "glitazone paradox'') [5], decreases circulating lipids such as free fatty acids (FFAs) via decreased FFA synthesis and increased triglyceride (TG) formation, ultimately ameliorating hyperglycemia by reversing lipotoxicity in liver and muscle [6]. PPARg agonism additionally modulates adipose endocrine activity by regulating adiponectin and resistin concentrations, whose functions include the modulation of liver and muscle insulin sensitivity [1]. Two genes, necdin and E2F4, thought to be integral in regulating cell differentiation processes, recently were identified as PPARg target genes following their modulation by rosiglitazone treatment (8 weeks) in humans [7]. Anti-inflammatory benefits also have been ascribed to PPARg activation, due to desirable reductions seen in pro-inflammatory cyto-kine and chemokines derived from adipose tissue. Indeed, in rodent models, anti-atheroslerotic effects have been observed, although in man the data currently remain ambiguous.

While three thiazolidinone (TZD)-derived PPARg agonists (troglitazone, rosig-litazone, pioglitazone) advanced to the market, the subsequent withdrawal of trog-litazone due to hepatotoxicity stimulated the search for non-TZD-containing structures, although no association of rosiglitazone or pioglitazone with this liability exists. Despite the unambiguous efficacy of PPARg full agonists, their intimate association with numerous adverse effects (cardiomegaly and tumorgenicity in preclinical species, along with weight gain, fluid retention, edema and its sequela clinically) has precluded their wider application. In actuality, multiple development candidates failed due to either edema- or carcogenicity-related liabilities. In response to these safety concerns, the FDA mandated that all clinical investigations of all PPAR agents, irrespective of subtype, may not exceed 6 months duration without the prior completion of 2-year carcinogenicity studies. While weight gain effects are ascribed, at least in part, to adipogenic effects, the precise mechanism(s) by which PPARg agonists cause fluid retention remains unclear. However, PPARg is expressed at high levels in the kidney's tubular nephron and mice lacking this target are resistant to TZD-mediated increases in weight gain and fluid retention, suggesting that the epithelial Na+ channel (ENaC) is a direct target of PPARg ligands [8,9].

Direct comparison of pioglitazone and rosiglitazone in dyslipidemic diabetics indicated that while both TZDs were comparable with respect to glycemic control, weight gain, edema and congestive heart failure, they had distinct effects on certain lipid parameters [10]. Specifically, pioglitazone treatment not only lowered TG levels while rosiglitazone therapy raised them modestly, but it also had superior effects on HDL-C and LDL-C concentrations. Outcomes studies utilizing piog-litazone (PROACTIVE) and rosiglitazone (RECORD) were initiated in order to assess whether chronic TZD treatment can also ameliorate cardiovascular risks. While the RECORD trial remains ongoing [11], the PROACTIVE study, while failing to meet its primary endpoints, did reduce overall all-cause mortality and adverse cardiovascular events but was complicated by a fourfold increase in the incidence of edema that exacerbated heart failure risk [12]. Other outcomes studies provided clear clinical evidence for p-cell preservation as a consequence of chronic TZD treatment, significantly lowering the risk of progression to frank diabetes in patients treated with troglitazone (TRIPOD) or pioglitazone (PIPOD) [13].

Newly reported PPARg agonists include nitrated analogs of prevalent fatty acids that function as putative high affinity endogenous ligands with potentially significant implications for the pathology of metabolic syndrome. Nitrolinoleic acid (1, LNO2) [14] and nitrooleic acid (2, OA-NO2) [15], detected at physiologically relevant levels in human plasma and urine, induced preadipocyte differentiation in 3T3-L1 adipocytes. TZD 3, while potently inducing TG accumulation in 3T3-L1 cells and correcting hyperglycemia in KKAy mice, was less cytotoxic in cultured rat hepatocytes than was rosiglitazone [16]. The potent benzoxazinone 4 normalized plasma glucose levels in db/db mice at doses as low as 1mg/kg/day [17,18]. The structurally novel pyran 5 resulted from efforts to identify non-TZD containing PPARg selective agonists [19]. Pyran 5 activated PPARg at potencies comparable to rosiglitazone (no in vivo data provided). Perhaps the most unusual PPARg agonist disclosed is the potent dimer 6 which was derived from a structurally related PPARa/g dual agonist [20]. Molecular modeling studies were used to clarify the origin of its PPARg binding selectivity. This dimeric structure retained modest PPARa and PPAR8 activities (EC50 values of 1200 and 1800 nM, respectively)

(hy EC50 = 133 nM) (hy EC50 ~ 100 nM)

(hy EC50 not reported) CO2H

(hy EC50 not reported) CO2H

.OMe

(hy EC50 not reported)

(hy EC50 not reported)

HO2C

HO2C

CO2H

CO2H

New potential applications for PPARg agonists include the pathogenesis of neurodegenerative diseases, such as multiple sclerosis (MS), Parkinson's (PD) and Alzheimer's (AD). While the data associated with PD is currently limited to beneficial effects in murine models [21], intriguing evidence suggestive of utility for PPARg agonists for MS [22] and AD [23-25] has recently appeared. On the basis of data from PPARg effects in experimental models that mimic MS, small clinical studies suggest that pioglitazone's benefits to MS patients may be ascribed to its anti-inflammatory effects [22] whereas a growing body of evidence has linked the pathogenesis of AD to hyperinsulinemia [25] in which clinical investigations of rosiglitazone treatment suggest a genetically defined subpopulation (APOE e4 negative patients) showed evidence of improved cognition [24].

2.2. PPARa

While PPARa is predominantly expressed in liver, it is also present in tissues (e.g. heart, skeletal muscle) that extract their energy requirements from lipids. Circulating fatty acids migrate to the liver where they are metabolized to provide fuel for peripheral tissues, a role elucidated in part through seminal studies of PPARa—/— mice [26].

While in rodents, PPARa agonists induce hepatic peroxisome proliferation leading to significant hepatoxicities, these effects fortunately are not recapitulated in man in part due to the 10-fold lower levels of PPARa expression in humans. Weak PPARa agonists such as fenofibrate, gemfibrozil and bezafibrate are remarkably effective at lowering TG levels with lesser effects on raising HDL-C in dyslipidemic populations [27]. These desirable effects are mediated through transcriptional activation of multiple genes that control these functions [2]. PPARa agonists also are known to possess antiinflammatory effects on vascular tissue and were proven to reduce cardiovascular risk in outcomes studies using gemfibrozil (VA-HIT) [28], fenofibrate (FIELD) [29] or bezafibrate (BIP) [30].

Comparatively, few new PPARa selective agonists have been reported (excluding patent disclosures). The 1,3-dicarbonyl 7 was shown to be a potent PPARa selective agonist and exhibited modest glucose-lowering activity in db/db mouse models [31]. Benzisoxazole 8 is a potent PPARa agonist, which was highly efficacious in hyper-lipidemic and hyperglycemic models [32]. Cyclic fibrate 9 also showed desirable utility in preclinical dyslipidemic models [33], while the PPARa-weighted agonist 10 was highly efficacious in the db/db model [34].

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