Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco Address Originator Bristol-Myers Squibb Co University of Milan . Istituto di Chimica Farmaceutica e Tossicologica Viale Abruzzi 42 Licensee Merck & Co Inc 20131 Milano . Italy Status Pre-registration Email: [email protected] . Indications Metabolic disorder, Non-insulin-dependent Current Opinion in Investigational Drugs 2005 6(4): diabetes © The Thomson Corporation ISSN 1472-4472 . Actions Antihyperlipidemic agent, Hypoglycemic agent, Bristol-Myers Squibb and Merck & Co are co-developing Insulin sensitizer, PPARα agonist, PPARγ agonist muraglitazar, a dual peroxisome proliferator-activated receptor-α/γ . agonist, for the potential treatment of type 2 diabetes and other Synonym BMS-298585 metabolic disorders. In November 2004, approval was anticipated as early as mid-2005. Registry No: 331741-94-7 Introduction [579218], [579221], [579457], [579459]. PPARγ is expressed in Type 2 diabetes is a complex metabolic disorder that is adipose tissue, lower intestine and cells involved in characterized by hyperglycemia, insulin resistance and immunity. Activation of PPARγ regulates glucose and lipid defects in insulin secretion. The disease is associated with homeostasis, and triggers insulin sensitization [579216], older age, obesity, a family history of diabetes and physical [579218], [579458], [579461]. PPARδ is expressed inactivity. The prevalence of type 2 diabetes is increasing ubiquitously and has been found to be effective in rapidly, and the World Health Organization warns that, controlling dyslipidemia and cardiovascular diseases unless appropriate action is taken, the number of sufferers [579216]. PPARα agonists are used as potent hypolipidemic will double to over 350 million individuals by the year compounds, increasing plasma high-density lipoprotein 2030. Worryingly, it is estimated that only half of sufferers (HDL)-cholesterol and reducing free fatty acids, are diagnosed with the condition [www.who.int]. Therefore, triglycerides, low-density lipoprotein (LDL)-cholesterol and prevention and treatment of type 2 diabetes mellitus the number of small dense LDL particles. The use of PPARγ represents a major clinical challenge. Although the activators in the treatment of type 2 diabetes is well pathophysiology of type 2 diabetes is not completely established. However, several unwanted effects are understood, over the past decade our understanding of fat associated to both treatments. In particular, weight gain, and sugar metabolism has greatly improved, and evidence edema, mild anemia and possible increased risk of suggests that, besides altered glucose metabolism, congestive heart failure often accompanies abnormalities in fat metabolism also play a central role in γ , α the pathogenesis of this disease [579204], [579206], PPAR stimulation while activation of PPAR results in 579221 [579210]. increased lipolysis and oxidation of fatty acids [ ], 579463 579464 579465 [ ], [ ], [ ]. The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor Given the importance of simultaneously controlling glucose superfamily. Three receptor isoforms have been cloned, homeostasis, insulin sensitization and lipid metabolism in α γ namely PPARα, -γ and -β/δ. Each subtype is expressed in a type 2 diabetes, activation of both PPAR and subtypes tissue-specific manner, and activity is exerted via binding to should be beneficial. This goal was initially attempted by a specific consensus DNA sequences, the peroxisome combination of two selective agonists [579206], [579216], α γ proliferator response elements (PPREs). PPARs are major [579466], [587224], but a number of PPAR / dual agonists regulators of lipid and glucose metabolism, and have been have also recently appeared in the literature; KRP-297, implicated in the regulation of insulin sensitivity and tesaglitazar (AstraZeneca plc), DRF-4158 (Dr Reddys symptoms of obesity, as well as in the control of food intake. Research Foundation), ragaglitazar, GW-409544, LY-465608 Thus, they have emerged as potential molecular targets for (Eli Lilly & Co) and LY-510929 (Eli Lilly & Co/Ligand the treatment of human metabolic disorders. In particular, Pharmaceuticals Inc [579204]. This evaluation focuses on α γ PPARα (present in the liver, heart and, to a lesser extent, muraglitazar (BMS-298585), a PPAR / dual agonist that is skeletal muscle) plays a significant role in the regulation of being developed by Bristol-Myers Squibb Co (BMS) in nutrient metabolism, including fatty acid oxidation, collaboration with Merck & Co Inc, for the oral treatment of gluconeogenesis and amino acid metabolism. The type 2 diabetes [454850], [535305], [535435]. modulation of PPARα function could be important for the regulation of compensatory insulin secretion, which is Synthesis and SAR suggested to be involved both in glucoregulation and Muraglitazar is a non-thiazolidinedione, oxybenzylglycine liporegulation. Deregulation of PPARα contributes to the PPARα/γ dual agonist. The synthesis of muraglitazar and pathogenesis of a variety of disease states, such as cardiac other analogs is detailed in WO-00121602, which describes hypertrophy and hyperlipidemia [579213], [579216], 30 reaction schemes. In one example of the synthetic route, muraglitazar was synthesized by reacting In addition, studies with different models demonstrated that 4-hydroxybenzaldehyde and 5-methyl-2-phenyloxazole-4- muraglitazar was able to normalize lipid content in the liver. ethanol in triphenylphosphine and diethylazodicarboxylate This was because PPARα activation enhanced lipid to yield the corresponding benzaldehyde intermediate, metabolism and lead to lipid lowering, which complements which was in turn reacted with 4-methoxy-N-benzylglycine the insulin sensitizing antidiabetic effects of PPARγ ethyl ester and sodium triacetoxyborohydride. The ester activation [454180], [454181]. group was removed by hydrolysis with sodium hydroxide to yield muraglitazar. A subsequent study was conducted in severely diabetic db/db mice administered muraglitazar and the selective Preclinical Development PPARγ agonist rosiglitazone (both at 10 mg/kg/day) for Binding studies with muraglitazar, based on a fluorescence 2 weeks. Fasting glucose was decreased by 51 and 30%, polarization assay, demonstrated IC50 values of 0.42 and 0.14 respectively. After an oral glucose challenge, the area under µM for PPARα and PPARγ, respectively. Muraglitazar did the glucose-response curve was decreased by 30 and 20%, not, however, show any significant activity towards PPARδ, respectively [541486]. In a parallel experiment on db/db mice or on a wide series of other nuclear hormone receptors [541486], muraglitazar (0.1 to 30 mg/kg/day for 4 weeks) [454098]. Potent agonistic activity at both PPARα and induced a progressive, dose-dependent lowering of plasma triglycerides, free fatty acids, glucose and insulin. It should PPARγ was demonstrated in transiently transfected Hep-G2 also be noted that treatment with muraglitazar (3 and CV-1 cell lines, respectively, where the respective EC 50 mg/kg/day) for 4 weeks normalized the level of plasma values of muraglitazar were 0.24 and 0.12 µM [454098], adiponectin, which was very low in db/db mice with respect [454181], [463529]. µ to normal C57BL/6 mice (3.9 versus 20 g/ml). In addition, the compound was able to decrease corticosterone levels in a Muraglitazar was tested in hamsters fed a high-fat diet dose-dependent manner. Finally, a reduction in urine output [454181], [463529]. This represents a highly predictive from 12 to 1.9 ml was obtained after administration of 30 animal model for the treatment of human hyperlipidemia. In mg/kg/day of muraglitazar. fact, unlike mice, these animals carry cholesterol in both HDL and LDL fractions, as do humans. Oral administration A study was conducted to verify whether muraglitazar was α of muraglitazar led to in vivo PPAR activation, as able to act directly upon macrophage foam cells, thereby confirmed by the induction of the acyl CoA oxidase gene retarding atherogenesis [542286]. Differentiating THP1 and suppression of the apoCIII gene in liver. This is in macrophage cells were treated for 24 h with 10 µM of either γ contrast to treatment with the PPAR agonist rosaglitazone, muraglitazar or rosiglitazone in vitro. The results indicated which did not cause induction of the acyl CoA oxidase gene. that 10 µM of muraglitazar induced the expression of In vivo, PPARγ activation was confirmed by the induction of multiple genes involved in reverse cholesterol transport, lipoprotein lipase and aP2 genes in white adipose tissue. namely CD36 (3.8-fold), apoE (5.9-fold), liver X receptor Administration of muraglitazar (10 mg/kg/day) for 4 weeks (LXR)α/β (3.8-fold), and ATP-binding cassette transporter 1 produced normalization of fasting plasma triglyceride (ABCA1) (2.8-fold). At the same concentration, rosiglitazone (-81%), very low-density lipoprotein (VLDL)+LDL- only weakly induced expression of CD36 (2.3-fold) and apoE cholesterol (-38%), free fatty acids (-60%) and fasting plasma (2.0-fold), and was not able to increase either LXRα/β or glucose (-19%) levels. At a dose of 30 mg/kg/day, fasting ABCA1 mRNA levels. When compared for their functional plasma glucose was lowered by 41%. In addition, activities, muraglitazar increased cholesterol efflux from administration of muraglitazar (10 mg/kg/day) for 6 weeks THP1 cells by 78%, while rosiglitazone increased it by only in fed animals caused triglyceride