Praveen, T K (2012) Pharmacological Evaluation of Some Novel Glitazones as Antidiabetic Agents. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.
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Abstract
Glitazones used to be the one of the most widely prescribed agents in the management of T2DM. These drugs score over other class of agents in this category because of their ability to reverse insulin resistance without stimulating the release of insulin from β-cells. They achieve this effect by reducing the hepatic glucose production and increasing the peripheral glucose utilization through their actions on PPAR receptors. Unfortunately, the clinically used TZDs, (troglitazone, pioglitazone and rosiglitazone) suffered with serious side effects. Several new approaches have, therefore, been made to address the problems associate with current TZDs. One of these is the development of molecules which have got both PPAR-α/γ dual agonistic activities. These molecules have been claimed to achieve a broad spectrum of metabolic effects by improving insulin resistance, hyperglycemia and atherosclerotic dyslipidemia. They are most beneficial in those T2DM patients with coexisting dyslipidemia, which is most common in patients with T2DM. In addition, PPAR-α promotes lipid oxidation and decreases adiposity and, therefore, neutralizes the PPAR-γ mediated weight gain and thereby provide better therapeutic benefits with minimization of the adverse effects associated with the PPAR-γ activation. In the present study eleven novel TZDs were synthesized and evaluated for their dual agonistic activities. Some of the key findings are summarized below; • A total of 257 molecules, including 5-(4-(3-phenoxypropoxy)benzyl) thiazolidine-2,4-dione, 5-(4-(3-phenoxypropoxy)benzylidene) thiazolidine-2,4-dione, 5-(4-(2-phenoxyethoxy) benzylidene)thiazolidine-2,4-dione, 5-(4-(2-phenoxyethoxy)benzyl) thiazolidine-2,4-dione derivatives and standard TZDs were subjected to docking studies against PPAR-α and γ LBD. The results of the study showed a good glide scores for most of the designed molecules which in many instances was better than the standard molecules for both the receptors, indicating a good amount of interactions with these receptors. • The post docking analysis showed various modes of hydrogen bond interaction and all the molecules showed qualitatively a similar pattern of per-residue interactions as that of respective standard molecules. Among these the compounds 10b, 10c, 10d, 10e, 10h and 10i showed exactly similar H-bond interactions as that of the full agonists, benzafibrate and rosiglitazone for PPAR-α and γ, respectively. These molecules were, therefore, considered to have a dual agonistic activity. • Based on the glide scores and other synthetic considerations, a total of eleven 5-(4-(3-phenoxypropoxy)benzylidene)thiazolidine-2,4-dione derivatives (10a-k), were selected and synthesized. These compounds are being reported for the first time after filing a patent. • The ADME properties of the synthesized compounds were analyzed in silico using QikProp programme. All the compounds showed good ADME predictions for all the parameters. Slight deviations were observed for a few compounds in some of the properties • PPAR-γ and PPAR-α competitive binding assays were carried out using time-resolved fluorescence resonance energy transfer (TR-FRET) PPAR-γ and PPAR-α competitive binding assay kits. The results of the study showed a moderate to good binding activity for all the synthesized compounds. Among these, compounds 10a, 10b, 10c and 10d showed better activity than the others and the results are comparable with the standards, rosiglitazone and benzafibrate. The docking studies have also predicted the possible dual agonistic activities for the compounds, 10b, 10c and 10d, 10e, 10h and 10j. • In the adipogenesis assay using 3T3-L1 preadipocytes, all the synthesized compounds (10a-k) showed adipocyte differentiation through activation of PPAR-γ. Among these, compound 10b showed the highest concentration of fat accumulation and it was comparable to the standard, rosiglitazone. • In the in vitro glucose uptake assay using rat hemidiaphragm, the synthesized compounds (10a-k) and rosiglitazone did not show any significant effects on the glucose uptake. These results supported the previous reports on the inability of TZDs to improve expression of GLUT-4. • In the in vitro α-glucosidase inhibition assay, compounds 10b and 10g inhibited the enzyme in a dose dependent manner and both showed better inhibition than the standard, acarbose. In the starch tolerance(in vivo α-glucosidase inhibition) test, compounds 10b and 10g at the dose levels of 50 and 100 mg/kg, p.o., significantly (p<0.05) prevented the starch induced elevation in blood glucose at 30, 60 and 120 min post starch administration in both normal and diabetic mice. The results were dose dependent and comparable to the standard, acarbose (50 mg/kg, p.o.). The docking studies of these two molecules with α-glucosidase LBD (PDB ID: 2QMJ), revealed the possible H-binding modes for these two molecules. Both the molecules formed H-bonds with Arg526 and Ash443 residues of LBD. The standard, acarbose, also formed H-bonds with these residues in addition to Asp203, Thr205, Asp327, Thr544 and Asp542 residues of the LBD. The α-glucosidase inhibition activity of these compounds may be attributed to H-bonding with Arg526 and Ash443 residues of the LBD. • In the acute oral toxicity study (Acute Toxic Class Method), both 10b and 10g, showed a LD50 values greater than 2000mg/kg (GHS category 5) in Swiss mice. • Compound 10b, in the in vivo antidiabetic study at the tested oral doses of 10, 50 and 100 mg/kg, showed a dose dependent effect and significantly reduced the STZ and high fat diet induced elevation in serum glucose, triglyceride, total cholesterol levels and retroperitoneal fat mass at all the dose levels and a significant effect on the body weight on the last week of treatment in the highest dose treated Group 5 animals (p<0.05). Rosiglitazone (10 mg/kg, p.o.) treated animals (Group 5) also showed a significant effect on the serum biochemistry. However, it showed no significant effects on the retroperitoneal fat mass and body weight changes. In conclusion, in the present study, the eleven compounds synthesized and being reported for the first time after filing a patent (Annexure-I) show moderate to good dual agonistic activities in the in silico and in vitro studies. Among these compounds, 10b shows a better PPAR-α and γ activity. In the in vivo antidiabetic study, also compound 10b at the tested oral doses of 10, 50 and 100 mg/kg, shows a dose dependent effect and significantly reduced the STZ and high fat diet induced elevation in serum glucose, triglyceride, total cholesterol levels, and retroperitoneal fat mass at all the dose levels and also had a significant effect on the body weight. Compound 10b at the highest tested dose of 100mg/kg, shows a very good antihyperglycemic and antihyperlipidemic activity, which was far better than rosiglitazone. In addition, oral LD50 of this molecule was found to be greater than 2000 mg/kg. Employing reasonably higher doses of this molecule to achieve the therapeutic goal may not, therefore, be an issue. However, further studies are needed to confirm its safety for long term use. In addition, compound 10b and 10g showed a very good in vitro and in vivo α-glucosidase inhibition (AGI) activity. AGIs are an important class of drugs for controlling PPG. Compounds 10b and 10g, therefore, have the potential to provide overall glucose control, including both FBG (through its PPAR effects) and PPG (through its alpha glucosidase inhibition effects). Such a potential is not possible with the existing drugs for T2DM.
| Item Type: | Thesis (Doctoral) |
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| Uncontrolled Keywords: | Pharmacological Evaluation, Some Novel Glitazones, Antidiabetic Agents. |
| Subjects: | PHARMACY > Pharmacology |
| Depositing User: | Subramani R |
| Date Deposited: | 19 Aug 2017 03:46 |
| Last Modified: | 27 Oct 2022 15:46 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/1765 |
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