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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
As a part of our programme, we were interested in developing new SPPARγM ligands with full PPARγ agonist activities as well as moderating the adverse side effects as fluid retention or body-weight gain. We have previously described a large series of α–ethoxyphenylpropionic acids bearing a benzoyl-indole core and found that many of them were full dual PPARα/γ agonists with higher selectivity for the PPARγ receptor15. Oxime ether introduction and enantiomeric resolution within this series of compounds allowed adjustment of the PPARα/γ potency ratio leading to best equally balanced PPARα/γ ligands. Unfortunately, despite high efficacy in an ob/ob mice model of T2D and dyslipidemia, similar to rosiglitazone and tesaglitazar, these compounds exhibited a disapproving benefit–risk ratio as they displayed a significant increase in body weight gain.