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Blood glucose was fine but the patients died
Published in Peter C. Gøtzsche, Richard Smith, Drummond Rennie, Deadly Medicines and Organised Crime, 2019
Peter C. Gøtzsche, Richard Smith, Drummond Rennie
Independent researchers saved the FDA from yet another diabetes scandal. Muraglitazar has a similar mechanism of action to the glitazones, and an FDA advisory committee recommended approval of the drug. However, independent researchers who analysed the trial data submitted to the FDA found that Bristol-Myers Squibb and Merck had produced flawed analyses and that the drug was harmful.40,41 The companies’ presentations to the advisory committee concluded that no significant excess risk of deaths or cardiovascular events occurred with muraglitazar. However, there was a two-fold increased risk in the composite outcome of death, heart attack or stroke and a seven-fold increase in heart failure (albeit with a wide confidence interval). The drug also increased weight and oedema, like the glitazones do. The Freedom of Information Act made the independent analysis possible, and it saved many lives. Although the FDA had already prepared an approval letter, it refused to approve the drug after this analysis.
Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Glitazars (Fig. 11.13) are dual PPAR α/γ agonists that improve the lipid profile and exert an antidiabetic action, similar to a combination of a fibrate and a TZD, so that they are considered as “two drugs in one” (Wilding, 2012). In glitazars, the thiazolidinedione moiety is replaced by a bioisosteric carboxylic acid. Ragaglitazar (Fig. 11.13, 11) was the first of this class reported, but was discontinued by Novo Nordisk and Dr. Reddy’s laboratories because of its adverse effects after detecting urinary bladder tumor in mice (Nanjan et al., 2018). After different clinical trials, in May 2006 the two glitazars most advanced in development at that time, muraglitazar (17, Pargluva™, developed by Brystol Myers Squibb) and tesaglitazar (12, Galida™, Astra Zeneca) were discontinued. In fact, 17 was associated with an increased incidence of heart failure, while tesaglitazar 12 was associated with decreased glomerular filtration (Conlon, 2006). Some other newer glitazars are aleglitazar 14, from Hoffmann-La Roche (Wilding, 2012), which was also discontinued in July 2013 after Phase III trials, and cevoglitazar 16 (Chen et al., 2010), (LBM-642, from Novartis AG), which failed to pass Phase I. Very recently, in June 2013, the Indian company Zydus Cadila has presented Lipaglyn™ (Saroglitazar 15), the first glitazar to be approved in the world, accepted for launch in India by the Drug Controller General of India (DCGI) for the treatment of diabetic dyslipidemia or hypertriglyceridemia in patients with type II diabetes not controlled by statins alone (Agrawal, 2014; Dwivedi et al., 2015; Sharma et al., 2015). Some glitazars.
Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Aurélie Hurtevent, Morgan Le Naour, Veronique Leclerc, Pascal Carato, Patricia Melnyk, Nathalie Hennuyer, Bart Staels, Monique Beucher-Gaudin, Daniel-Henri Caignard, Catherine Dacquet, Nicolas Lebegue
The in vivo effect of test compounds was determined by measuring glycaemia, triglyceridemia, insulinemia, and body weight using ob/ob mice (Table 3). The ob/ob mice were obese, insulin resistant with hypertriglyceridaemia and hyperglycaemia, and have been used as a rodent model of obesity-induced insulin resistance. In this model, mice were dosed orally with either synthesised compounds or standard reference compounds (rosiglitazone and muraglitazar) at 8.4 µMkg−1 and 3 mgkg−1 respectively for 4 days. As a side effect index, body weight was also measured daily, and body weight variation was calculated as a percentage of the difference in body weight between days 4 and 0. The results were normalised to those obtained with rosiglitazone in the same experiment, which was set to 100%. Benzoyl derivatives 32a, 41a and 42a were not evaluated in vivo with regard to their low absorption values with CaCO2 cells (< 25%), an in vitro model predicting membrane permeability38. In this model, oxime derivatives displayed good percentages of absorption ranging from 65% to 100%, except compound 45a with only 31% in CaCo2 permeability. Racemate 39a bearing an oxime function displayed in vivo profile similar to reference compounds, but without promoting body weight gain compared with rosiglitazone and muraglitazar. Interestingly, incorporation of O-methyl oxime ether led to compound 40a showing a slight improvement of the pharmacological activity in terms of reducing triglyceridemia, glycaemia and insulinemia. However, no improvement was obtained in terms of body weight gain showing the same level as muraglitazar and suggesting the same side effects. Introduction of a trifluoroethoxy group led to less potent racemates 39 b and 40 b but with a sharp decrease in body-weight gain compared with rosiglitazone. These results are consistent with the results obtained in the PPARα and γ gene reporter assays. Indeed, incorporation of substituents such as methyl oxime ether and trifluoroethoxy group are benefiting for PPAR activity regulation and so for effective management of dyslipidemia without inducing body weight gain. The same results were observed with the (S)-derivative 44 b in which O-methyl oxime ether allowed significant decreases in serum triglyceride, glucose and insulin levels compared with its oxime counterpart 43a. The CF3 group incorporation, beyond keeping a good in vivo efficacy, provided a robust reduction of body weight induced with compound 44a, strengthening the beneficial pharmacological effect of C-H bond replacement with fluorine. Compound 44 b may be considered as a SPPARγM since this full PPARγ agonist retains the insulin-sensitizing and glucose-lowering actions while mitigating or eliminating the undesirable side effects. Finally, only the (R)-stereoisomer 45a was engaged in the in vivo experiments and was found inactive as the whole of PPAR ligands described in the literature1.