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Myopathy and rhabdomyelosis are well recognized but comparatively rare adverse events associated with all fibrates, which are weak PPARa agonists. As the mechanism underlying these adverse effects is poorly understood (PPARa expression in muscle is very low), it remains an open question as to whether a potent PPARa hyperlipidemic agent would exacerbate the frequency and severity of clinical myotoxicity. An in vitro model using differentiated rat skeletal muscle cultures was developed to evaluate myotoxicity [35]. In this assay, high-affinity PPARa agonists induce myotoxicities at lower drug concentrations than do weaker PPARa agonists (1 nM for 11 versus micromolar levels for bezafibrate and gemfibrozil).

PPARa agonists show promise in treating individuals afflicted with hepatitis C virus (HCV), a major cause of liver disease. As HCV particles are associated with circulating LDL [36] and the expression of hepatic PPARa in HCV-positive individuals is dramatically impaired [37], a pilot study (8 week) treating HCV patients with bezafibrate was initiated that showed a statistically significant reduction in HCV mRNA titers [38].

2.3. PPAR8

Of the PPAR isoforms, the biological function of the PPAR8 subtype, which is expressed ubiquitously, remains the most controversial in part because only recently were sufficiently potent and selective ligands identified and as mechanistic studies yielded conflicting results. For instance, PPAR8 null mice are prone to epithelial cell proliferation [39], suggesting that a PPAR8 agonist would inhibit proliferation whereas in vitro, high affinity PPAR8 agonists stimulate proliferative changes in human breast and prostate cells [40]. Treatment of Apd"in mice, which are predisposed to colon polyp formation, with a PPAR8 agonist significantly increased the number and size of polyps formed [41], a result consistent with related studies [42]. Other investigations using PPAR8—/— mice, however, yielded conflicting data, suggesting that PPAR8 lacks a specific role in cancer but instead decreased adiposity remarkably in all depots examined [43]. The changes in adiposity are consistent with other observations that PPAR8 agonism induces genes associated with fatty acid p-oxidation in muscle fibers and can ameliorate diabetes in ob/ob mice [44].

GW501516 (12), and its fluorinated analog GW0742 (13), were the first potent PPAR8 agonists identified and their discovery was guided by crystallographic studies [45]. T0913659 (14) is a potent but modestly PPAR8 selective agonist [46]. A PPARa selective agonist served as inspiration for 15, which was another potent PPAR8-selective agonist [47].

13: GW0742 R= F (h6 EC50 = 1 nM) (hy / hy / hS EC50 = 510 / 150° / 9 nM)

13: GW0742 R= F (h6 EC50 = 1 nM) (hy / hy / hS EC50 = 510 / 150° / 9 nM)

These new selective agents proved invaluable for the characterization of PPAR8 effects, suggesting that PPAR8 agonism may attenuate metabolic syndrome-related abnormalities. For instance, GW0742 reduced atherosclerosis in murine models [48]. In primates, GW501516 increased HDL-C significantly (80%), while lowering LDL-C substantially (-29%) [49,50]. Similarly, T0913659 exhibited beneficial lipid effects in monkeys [46]. In LDLR-/— mice, PPAR8 agonism was shown to increase CD36 expression and decrease inflammation, but had no beneficial effects on vascular lesion formation nor to lower macrophage lipid accumulation [51]. GW501516 has advanced to Phase II clinical study for dyslipidemia; results from preliminary trials (6 weeks) showed significant reductions in total cholesterol, TG and apolipoprotein B concentrations [52].

As noted previously, myopathy is an adverse event clinically associated with PPARa agonist monotherapy, although its etiology is poorly understood. To date, no reports of myopathy ascribed to PPAR8 have appeared, despite its abundant expression levels in muscle fibers and PPAR8 agonist effects on lipid accumulation. However, in the previously described rat-cultured myotube assay, GW501516 also had significant effects, although these could not be rigorously ascribed to PPAR8 agonism [35]. Ultimately, given the limitations of preclinical tools, clinical evaluation of potent PPAR8 selective agonists is necessitated to generate unambiguous evidence regarding potential myopathic liabilities of PPAR8 agonism.

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