Effect of 1-[4-[2-(4-Bromobenzenesulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcyclohexyl)urea (I₄), a New Synthetic Sulfonylurea Compound, on Glucose Metabolism in vivo and in vitro

Abstract

Background:

1-[4-[2-(4-Bromobenzenesulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcyclohexyl)urea (I₄, CAS 865483-06-3), a totally synthetic new sulfonylurea compound, incorporating part of the hypoglycemic structure of glime-piride (CAS 93479-97-1) and having anti-TXA₂ receptor properties, was designed and synthesized. Its hypoglycemic property had not been reported yet.

Aim:

To study the hypoglycemic effects of I₄ and its primary mechanisms of action.

Methods:

A rat model of type 2 diabetes was established by intraperitoneal injection of small doses of streptozntocin combined with high calorie feeding. Normal fasted mice and type 2 diabetic rats were used to assay the hypoglycemic actions of I₄. Blood glucose and immunoreactive insulin concentrations were measured and the effects of I₄ on insulin release from rat isolated pancreatic islets were examined. A liver cell line, Hep G2, was used to examine effects on glucose consumption, glycogen synthesis and glucokinase activity.

Results:

Oral administration of I₄ (1–10 mg/kg) produced a marked, dose-dependent reduction in blood glucose in normal mice and type 2 diabetic rats and improved oral glucose tolerance. Plasma insulin concentrations were increased, and I₄ increased insulin release from rat isolated pancreatic islets and from the isolated perfused rat pancreas. I₄ (1–100 iimol • L⁻¹) also produced an insulin-independent increase in glucose consumption by Hep G2 cells, increased glycogen synthesis and glucokinase activity of these cells. Glimepiride produced similar effects on glucose consumption and glycogen synthesis but did not facilitate glucokinase activity of Hep G2 cells.

Conclusion:

I₄ markedly improved glucose metabolism in normal animals and type 2 diabetic rats, probably by increasing insulin secretion and stimulating hepatic glucose uptake and glycogen synthesis.

Key words

1-[4-[2-(4-Bromobenzenesulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methyl-cyclohexyl)urea - CAS 865483–06–3 - Glucokinase - I₄, hypoglycemic effect - Pancreatic islets

• References

• 1 Grimaldi A, Heurtier A. Epidemiology of cardiovascular complications of diabetes. Diabetes Metab. 1999; Jun 25 (Suppl 3:) 12-20
• 2 Donnelly R, Emslie-Smith AM, Gardner ID, Morris AD. ABC of arterial and venous disease. Vascular complications of diabetes. BMJ. 2000; Apr 15 320 (7241) 1062-6
• 3 Haffner SM, Lehto S, Ronnemaa T, Pyroala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998; Jul 23 (339) 4: 229-34
• 4 Winocour PD. Platelets, vascular disease, and diabetes mellitus. Can J Physiol Pharmacol. 1994; Mar 72 (3) 295-303
• 5 Sobol AB, Watala C. The role of platelets in diabetes related vascular complications. Diabetes Res Clin Pract. 2000; Sep 50 (1) 1-16
• 6 Serebruany VL, Malinin AI, Pokov A, Barsness G, Hanley DF. Effects of Clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in diabetic patients: The plavix use for treatment of diabetes (PLUTO-Diabetes) trial. Am Heart]. 2008; Jan 155 (1) 93.el-7
• 7 Vinik AI, Vinik E. Prevention of the complications of diabetes. Am J Manag Care. 2003; Mar 9: S63-80
• 8 Scognamiglio R, Avogaro A, De Kreutzenberg SV, Negut C, Palisi M, Bagolin E et al. Effects of treatment with sulfonylurea drugs or insulin on ischemia-induced myocardial dysfunction in type 2 diabetes. Diabetes. 2002; Mar 51 (3) 808-12
• 9 Zingg W, Leibel BS. Modification of platelet adhesion by antiplatelet drugs helps prevent cardiovascular complications of diabetes mellitus. Med Hypotheses. 1985; Oct 18 (2) 119-27
• 10 Melero PS, De Antolinez AN. Oral anti-diabetes medicines, an update. Rev. Enferm. 2008; Mar 31 (3) 7-10
• 11 Monami M, Balzi D, Lamanna C, Barchielli A, Masotti G, Buiatti E et al. Are sulphonylureas all the same? A cohort study on cardiovascular and cancer-related mortality. Diabetes Metab Res Rev. 2007; Sep 23 (6) 479-84
• 12 Green JB, Feinglos MN. Are sulfonylureas passé?. Curr Diab Rep. 2006; Nov 6 (5) 373-7
• 13 Guerra SD, Grupillo M, Masini M, Lupi R, Bugliani M, Torri S et al. Gliclazide protects human islet beta-cells from apoptosis induced by intermittent high glucose. Diabetes Metab Res Rev. 2007; Mar 23 (3) 234-8
• 14 Johannes CB, Koro CE, Quinn SG, Cutone JA, Seeger JD. The risk of coronary heart disease in type 2 diabetic patients exposed to thiazolidinediones compared to metformin and sulfonylurea tients . Pharmacoepidemiol Drug Saf. 2007; May (5) 504-12
• 17 Kabadi MU, Kabadi UM. Efficacy of sulfonylureas with insulin in type 2 diabetes mellitus. Ann Pharmacother. 2003; Nov 37 (11) 1572-6
• 16 Krauss H, Kozlik J, Grzymislawski M, Sosnowski P, Mikrut K, Piatek J. The influence of glimepiride on the oxidative state of rats with streptozotocin-induced hyperglycemia. Med Sci Monit. 2003; Nov 9 (11) BR389-93
• 17 Zhang HB, Zhang YA, Wu GZ, Zhou JP, Huang WL, Hu XW. Synthesis and biological evaluation of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups as potential hypoglycemic agents. Bioorg Med ChemLett. 2009; 19 (6) 1740-4
• 18 Zhang WP, Wu GZ, Liu GQ. Effects and mechanisms of compound G004 on experimental thrombosis. China Clin Pharmacol Ther. 2005; 10: 162-7
• 19 Ye Fei. Pharmacological Experiment Methods and Technology in Diabetes Mellitus. In: Zhang JT. (editor) Modern Pharmacological Experiment Methods. Beijing: Peking medical university and Chinese academy of medicine science press; 1998. p 984-987
• 20 Wu GZ, Forman BL. Study on effect and its mechanism of deoxyadenosine on insulin secretion of rat isolated islets of langerhans. J China Pharm Univ. 1996; 27: 421-4
• 21 Grodsky GM, Fanska RE. The in vitro perfused pancreas. Methods Enzymol. 1975; 39: 364-72
• 22 James KM, Charles EO, Douglas EE. Thermostable continuous coupled assay for measuring glucose using glucoki-nase and glucose–6-phosphate dehydrogenase from the marine hyperthermophile Thermotoga maritime. Anal Bio-chem. 2003; Jul 15 318 (2) 196-203
• 23 Ye Fei. Determination of Glycogen Synthesis and Gluco-neogenesis. In: Zhang JT. (editor) Modern Pharmacological Experiment Methods. Beijing: Peking medical university and Chinese academy of medicine science press; 1998. p 1006-1007
• 24 Guerra SD, Parentini C, Bracci C, Lupi R, Marselli L, Aragona M et al. Insulin release from isolated human islets after acute or prolonged exposure to glimepiride. Acta Dia-betol. 2000; 37 (3) 139-41
• 25 Lupi R, Marchetti P, Giannarelli R, Coppelli A, Teilini C, Guerra SD et al. Effects of glibenclamide and metformin (alone or in combination) on insulin release from isolated human pancreatic islets. Acta Diabetol. 1997; Mar 34 (1) 46-8
• 26 Nesher R, Cerasi E. Modeling Phasic Insulin Release: Immediate and Time-Dependent Effects of Glucose. Diabetes. 2002; Feb (Suppl 1) S53-9
• 27 Prato SD, Marchetti P, Riccardo CB. Phasic Insulin Release and Metabolic Regulation in Type 2 Diabetes. Diabetes. 2002; Feb 51 (suppl 1) S109-9
• 28 Luzi L, DeFronzo RA. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol. 1989; Aug 257 (2 Pt 1) E241-6
• 29 Feldman JM, Lebovitz HE. Appraisal of the extrapancreatic actions of sulfonylureas. Arch Intern Med. 1969; Mar 123 (3) 314-22
• 30 Beck-Nielsen H, Hother NO, Pedersen O. Mechanism of action of sulphonylureas with special reference to the extrapancreatic effect: an overview. Diabet. Med. 1988; Oct 5 (7) 613-20
• 31 Garvey WT. Glucose transport and NIDDM. Diabetes Care. 1992; Mar 15 (3) 396-417
• 32 Muller G, Wied S, Wetekam EM, Crecelius A, Unkelbach A, Punter J et al. Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in vitro by the sulphonylureas, glimepiride and glibenclamide, is correlated with modulations of the cAMP regulatory cascade. Biochem Pharmacol. 1994; Aug 30 48 (5) 985-96
• 33 Wu GZ, Hong G, Wang GJ. Hypoglycemic effect and its mechanism of novel compound G-003. Chin Pharmacol Bull. 2004; 20: 1026-30
• 34 Kunte H, Schmidt S, Eliasziw M, Zoppo GJD, Simard JM, Masuhr F et al. Sulfonylureas improve outcome in patients with type 2 diabetes and acute ischemic stroke. Stroke. 2007; Sep 38 (9) 2526-30
• 35 Del GS, Grupillo M, Masini M, Lupi R, Bugliani M, Torri S et al. Gliclazide protects human islet beta-cells from apop-tosis induced by intermittent high glucose. Diabetes Metab Res Rev. 2007; Mar 23 (3) 234-8