During the last decade, a major investment was made by the pharmaceutical d24 industry to develop sa

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Nabajyoti Deka , 1 Swapnil Bajare , 2 Jessy Anthony , 3 Amrutha Nair , 3 Anagha Damre , 4 Dharmeshkumar Patel , 5 Chandrika B-Rao , 5 H. Sivaramakrishnan , 1 Shivaprakash Jagalur Mutt , 3,6 Chandan Wilankar , 3 and Rosalind Marita 7
1 Department of Medicinal Chemistry, Piramal Life Sciences Limited, 1 Nirlon Complex, Goregaon East, Mumbai 400 063, India 2 Lupin Limited, Mumbai, India 3 Department of Pharmacology, Piramal Life Sciences Limited, d24 1 Nirlon Complex, Goregaon East, Mumbai 400 063, India 4 Department of DMPK, Piramal d24 Life Sciences Limited, 1 Nirlon d24 Complex, Goregaon East, Mumbai 400 063, India 5 Department d24 of Discovery Informatics, Piramal Life Sciences Limited, 1 Nirlon Complex, Goregaon East, Mumbai 400 063, India 6 Institute of Biomedicine, Department of Physiology, Biocenter of Oulu, Faculty of Medicine, Oulu University, P.O. Box 5000, Aapistie 7, 90014 Oulu, Finland 7 Department of Biochemistry, Haffkine Institute for Training, Research and Testing, Parel, Mumbai 400 012, India
Metabolic syndrome is a widely prevalent multifactorial disorder associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. High plasma levels of insulin and glucose due to insulin resistance are a major component of the metabolic disorder. Thiazolidinediones (TZDs) are potent PPAR γ ligand and used as insulin sensitizers in the treatment of type 2 diabetes mellitus. They are potent insulin-sensitizing agents but due to adverse effects like hepatotoxicity, a safer alternative of TZDs is highly demanded. Here we report synthesis of N-(6-(4-(piperazin-1-yl)phenoxy)pyridin-3-yl)benzenesulfonamide derivatives as an alternate remedy for insulin resistance. 1. Introduction
Metabolic d24 disorder is a highly widespread clinical entity. Although d24 obesity and insulin resistance are not synonymous with the metabolic d24 syndrome, d24 they are integral features in this derangement d24 of adipocyte physiology and carbohydrate metabolism. PPARs play a key role in adipocyte differentiation and insulin sensitivity [ 1 ]. They are lipid sensors known to govern numerous d24 biological processes. There are three PPAR subtypes ( α , β , and γ ) and they regulate the expression d24 of numerous genes involved in a variety of metabolic pathways [ 2 ]. Roles of PPAR α and PPAR γ are now quite well known, particularly since their pharmacologic ligands have been marketed. PPAR α and PPAR γ are the target of the lipid-normalizing class of fibrates (e.g., fenofibrate and gemfibrozil) and the antidiabetic class of thiazolidinediones (e.g., rosiglitazone and pioglitazone), respectively [ 3 ]. PPAR γ is expressed most abundantly in adipose tissue and is a master regulator of adipogenesis [ 4 , 5 ]. Thiazolidinediones (Figure 1 ), selective activators of PPAR γ , have been marketed as antidiabetic drugs. They enhance insulin action, improve glycemic control, reduce the level of glycohemoglobin (HbA 1C ), and have variable effects d24 on serum triglyceride levels in type 2 diabetic patients. Despite their efficacy, they possess a number of side effects [ 6 , 7 ], including weight gain and peripheral edema, increased risks of congestive heart failure, and increased rate of bone fracture. The weight gain is likely due to multiple interacting factors, including increased adiposity and fluid retention. Moreover, the assumption that TZD treatment causes a significant increase d24 in the risk of myocardial infarction and an increase in the risk of death from cardiovascular events in patients with type 2 diabetes. More importantly, TZDs treatment was recently shown to decrease bone formation and accelerated bone loss in healthy and insulin resistant individuals [ 8 ]. Such major safety concerns d24 led to development failure of a large number of PPAR agonists.
During the last decade, a major investment was made by the pharmaceutical d24 industry to develop safer PPAR γ modulator. This effort led to the description of several unique non-TZD partial PPAR γ agonists with a potential for reduced side effects. d24 INT131 (Figure 2 ), for example, a novel, nonthiazolidinedione (TZD), selective peroxisome proliferator-activated receptor gamma (PPAR γ ) modulator [ 9 ], is in development by InteKrin Therapeutics Inc. for the treatment of type 2 diabetes mellitus. Here we report synthesis of N-(6-(4-(piperazin-1-yl)phenoxy)pyridin-3-yl)benzenesulfonamide derivatives as an alternate d24 remedy for insulin resistance. Compounds were screened for adipogenesis in 3T3-L1 adipocytes and in PPAR γ transactivation assay. They were fou