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  • br Introduction Type Diabetes mellitus T DM

    2021-04-17


    Introduction Type 2 Diabetes mellitus (T2DM) is a metabolic disorder that raises blood glucose level for a prolonged time. Cytochrome Oxidase Activity Colorimetric Assay Kit T2DM is associated with acute complications like ketoacidosis, hyposmolar coma, chronic complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes, consequently may be fatal if not treated. T2DM has been now considered as a major human health concern, estimated that on 2013, 382 million people have diabetes worldwide. In 2014, the International Diabetes Federation (IDF) estimated that diabetes resulted in 4.9 million deaths. The World Health Organization (WHO) estimated that diabetes resulted in 1.5 million deaths in 2012, making it the 8th leading cause of death. . The greatest increase in rates is expected to occur in Asia and Africa, where most people with diabetes will probably be found by 2030 [1] (see Scheme 1, Scheme 2, Table 1) At present, pharmacological treatments for type 2 diabetes are based on increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and Cytochrome Oxidase Activity Colorimetric Assay Kit of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion. Glucagon-like peptide-1 (GLP-1)-based therapies (eg dipeptidyl peptidase-4 [DPP-4] inhibitors, GLP-1 receptor agonists) affect glucose control through several mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon and of food intake [2]. Dipeptidyl peptidase-4 (DPP4, also known as CD26) is a membrane glycoprotein that is well known for its role in the catalytic degradation of incretins. DPP4 inhibitors, as a class of oral antidiabetic medications, have been accepted worldwide, owing to their ease of administration, modest effects on HbA1c and lack of serious side effects. DPP4 inhibition in experimental models has uniformly demonstrated cardioprotective effects. [3] [4]. DPP-4 is a transmembrane glycoprotein that forms a homodimer or tetramer on the plasma membrane and cleaves N-terminal dipeptides from proteins with proline or alanine as the penultimate (P1) amino acids. DPP4 is highly conserved among species in terms of amino acid sequence. DPP4 has a 6-amino-acid N-terminal cytoplasmic domain (AA1–6), a 22-residue transmembrane domain (AA7–29), and a large C-terminal extracellular domain. The extracellular component contains α/β-hydrolase domain and an eight-blade β-propeller domain [5]. This domain is responsible for its dipeptidyl-peptidase activity and its binding to proteins such as adenosine deaminase (ADA) and fibronectin. Residue 294 and residues 340–343 within the cysteine-rich segment have been shown to be essential for ADA binding [6,7] while residues 630, 708 and 740 are critical for the catalytic activity of DPP4 [8]. At present five competitive reversible inhibitors i.e. Sitagliptin, Alogliptin, Vildagliptin, Linagliptin and saxagliptin (Fig. 1) are in market with USFDA approvals in different years while many more are in different phases of clinical trials. Saxagliptin, Sitagliptin and Linagliptin are licensed in most of the world, Vildagliptin is licensed in Europe, Latin America and Alogliptin is licensed in Japan and US [9]. Alogliptin is a potent, selective inhibitor of the serine protease DPP-4 [10]. Alogliptin or (2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl] benzonitrile) (C, Fig. 2), a potent (IC50 < 10 nM) and selective inhibitor (selectivity > 10,000 over DPP-8 and 9) was identified by replacing the quinazolinone moiety of another inhibitor D with a pyrimidine dione [11]. We have designed N-benzylated (B, Fig. 2) and N-methylated pyrimidine diones (A, Fig. 2) by taking Alogliptin (C) and Quinazoline scaffold (D) as reference moieties.
    Materials and methods
    Result and discussion The peptidase activity of the enzyme has been evaluated in the enzymatic assay. Some compounds had shown inhibitory activity in significant range (3c, 3d, 3e, 5c). Few other compounds (3a, 5d) have demonstrated DPP-4 inhibition in moderate range (Table 3). Val pro was taken as standard for the assay which has 33.05% of DPP-4 inhibitory activity.