Discovery of fructose-1,6-bisphosphatase inhibitors for the treatment of type 2 diabetes

Current Opinion in Drug Discovery and Development

Volumn 10, Issue 4, 2007, Pages 430-437

  Van Poelje, P D ^a   Dang, Q ^a   Erion, M D ^a  

^a Metabasis Therapeutics Inc   (United States)

Author keywords

AMP mimetic; Antihyperglycemic; CS 917; Fructose 1,6 bisphosphatase inhibitor; Gluconeogenesis; Hepatic glucose production; Structure based drug design

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; ADENOSINE PHOSPHATE; ANTIDIABETIC AGENT; CS 917; FRUCTOSE 1,6 BISPHOSPHATASE INHIBITOR; GLIBENCLAMIDE; GLUCOSE; MANAGLINAT DIALANETIL; MB 06322; OC 252324; PIOGLITAZONE; UNCLASSIFIED DRUG;

DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG EFFICACY; DRUG POTENTIATION; DRUG STRUCTURE; GLUCOSE BLOOD LEVEL; HUMAN; IC 50; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; REVIEW; STRUCTURE ANALYSIS; TREATMENT OUTCOME;

ANIMALS; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; ENZYME INHIBITORS; FRUCTOSE-BISPHOSPHATASE; HUMANS;

EID: 34447632817     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (49)

1. Moller DE: New drug targets for type 2 diabetes and the metabolic syndrome. Nature (2001) 414(6865):821-827.
2. Wagman AS, Nuss JM: Current therapies and emerging targets for the treatment of diabetes. Curr Pharm Des (2001) 7(6):417-450.
3. Barf T: Intervention of hepatic glucose production. Small molecule regulators of potential targets for type 2 diabetes therapy. Mini Rev Med Chem (2004) 4(8):897-908.
4. Jeng CY, Sheu WH, Fuh MM, Chen YD, Reaven GM: Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM. Diabetes (1994) 43(12):1440-1444.
5. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS et al: Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial. Ann Intern Med (1998) 128(3):176-185.
6. Firth RG, Bell PM, Marsh HM, Hansen I, Rizza RA: Postprandial hyperglycemia in patients with noninsulin-dependent diabetes mellitus: Role of hepatic and extrahepatic tissues. J Clin Invest (1986) 77(5):1525-1532.
7. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J: Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med (1992) 326(1):22-29.
8. 13C nuclear magnetic resonance techniques, this study provides conclusive evidence that the rate of gluconeogenesis is elevated in patients with type 2 diabetes.
9. El-Maghrabi MR, Gidh-Jain M, Austin LR, Pilkis SJ: Isolation of a human liver fructose-1,6-bisphosphatase cDNA and expression of the protein in Escherichia coli. Role of ASP-118 and ASP-121 in catalysis. J Biol Chem (1993) 268(13):9466-9472.
10. Van Schaftingen E, Hers H-G: Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-bisphosphate. Proc Natl Acad Sci USA (1981) 78(5):2861-2863.
11. Ke HM, Liang JY, Zhang YP, Lipscomb WN: Conformational transition of fructose-1,6-bisphosphatase: Structure comparison between the AMP complex (T form) and the fructose 6-phosphate complex (R form). Biochemistry (1991) 30(18):4412-4420. • Provides a detailed X-ray crystallographic analysis describing the molecular mechanism by which AMP inhibits FBPase.
12. Gidh-Jain M, Zhang Y, van Poelje PD, Liang JY, Huang S, Kim J, Elliott JT, Erion MD, Pilkis SJ, Raafat el-Maghrabi M et al: The allosteric site of human liver fructose-1,6-bisphosphatase. Analysis of six AMP site mutants based on the crystal structure. J Biol Chem (1994) 269(44):27732-27738.
13. Pilkis SJ, Claus TH: Hepatic gluconeogenesis/glycolysis: Regulation and structure/function relationships of substrate cycle enzymes. Ann Rev Nutr (1991) 11:465-515.
14. el-Maghrabi MR, Lange AJ, Kümmel L, Pilkis SJ: The rat fructose-1,6-bisphosphatase gene. Structure and regulation of expression. J Biol Chem (1991) 266(4):2115-2120.
15. Kodama H, Fujita M, Yamazaki M, Yamaguchi I: The possible role of age-related increase in the plasma glucagon/insulin ratio in the enhanced hepatic gluconeogenesis and hyperglycemia in genetically diabetic (C57BL/KsJ-db/db) mice. Jpn J Pharmacol (1994) 66(3):281-287.
16. Pilkis SJ, McGrane MM, Kountz PD, el-Maghrabi MR, Pilkis J, Maryanoff BE, Reitz AB, Benkovic SJ: The effect of arabinose 1,5-bisphosphate on rat hepatic 6-phosphofructo-1-kinase and fructose-1,6-bisphosphatase. Biochem Biophys Res Commun (1986) 138(1):159-166.
17. Choe JY, Nelson SW, Arienti KL, Axe FU, Collins TL, Jones TK, Kimmich RD, Newman MJ, Norvell K, Ripka WC, Romano SJ et al: Inhibition of fructose-1,6-bisphosphatase by a new class of allosteric effectors. J Biol Chem (2003) 278(51):51176-51183.
18. Wright SW, Hageman DL, McClure LD, Carlo AA, Treadway JL, Mathiowetz AM, Withka JM, Bauer PH: Allosteric inhibition of fructose-1,6-bisphosphatase by anilinoquinazolines. Bioorg Med Chem Lett (2001) 11(1):17-21.
19. Wright SW, Carlo AA, Carty MD, Danley DE, Hageman DL, Karam GA, Levy CB, Mansour MN, Mathiowetz AM, McClure LD, Nestor NB et al: Anilinoquinazoline inhibitors of fructose 1,6-bisphosphatase bind at a novel allosteric site: Synthesis, in vitro characterization and X-ray crystallography. J Med Chem (2002) 45(18):3865-3877.
20. Rosini M, Mancini F, Tarozzi A, Colizzi F, Andrisano V, Bolognesi ML, Hrelia P, Melchiorre C: Design, synthesis, and biological evaluation of substituted 2,3-dihydro-1H-cyclopenta[b] quinolin-9-ylamine related compounds as fructose-1,6-bisphosphatase inhibitors. Bioorg Med Chem (2006) 14(23):7846-7853.
21. Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G: Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes (1991) 40(10):1259-1266.
22. Erion MD, van Poelje PD, Dang Q, Kasibhatla SR, Potter SC, Reddy MR, Reddy KR, Jiang T, Lipscomb WN: MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes. Proc Natl Acad Sci USA (2005) 102(22):7970-7975. •• Provides a description of the structure-guided design of CS-917, the first drug of the FBPase inhibitor class to enter clinical evaluation.
23. Henin N, Vincent MF, Van den Berghe G: Stimulation of rat liver AMP-activated protein kinase by AMP analogues. Biochim Biophys Acta (1996) 1290(2):197-203.
24. Vincent MF, Bontemps F, Van den Berghe G: Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes. Biochem J (1992) 281(Pt 1):267-272.
25. Vincent MF, Erion MD, Gruber HE, Van den Berghe G: Hypoglycaemic effect of AICAriboside in mice. Diabetologia (1996) 39(10):1148-1155.
26. Pold R, Jensen LS, Jessen N, Buhl ES, Schmitz O, Flyvbjerg A, Fujii N, Goodyear LJ, Gotfredsen CF, Brand CL, Lund S: Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes (2005) 54(4):928-934.
27. Wright SW, Carlo AA, Danley DE, Hageman DL, Karam GA, Mansour MN, McClure LD, Pandit J, Schulte GK, Treadway JL, Wang IK et al: 3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid: An allosteric inhibitor of fructose-1,6-bisphosphatase at the AMP site. Bioorg Med Chem Lett (2003) 13(12):2055-2058.
28. von Geldern TW, Lai C, Gum RJ, Daly M, Sun C, Fry EH, Abad-Zapatero C et al: Benzoxazole benzenesulfonamides are novel allosteric inhibitors of fructose-1,6-bisphosphatase with a distinct binding mode. Bioorg Med Chem Lett (2006) 16(7):1811-1815.
29. Lai C, Gum RJ, Daly M, Fry EH, Hutchins C, Abad-Zapatero C, von Geldern TW: Benzoxazole benzenesulfonamides as allosteric inhibitors of fructose-1,6-bisphosphatase. Bioorg Med Chem Lett (2006) 16(7):1807-1810. • Describes X-ray crystallographic studies indicating an inhibitor binding site in close proximity to the AMP site.
30. Reddy MR, Erion MD: Computer-aided drug design strategies used in the discovery of fructose 1, 6-bisphosphatase inhibitors. Curr Pharm Des (2005) 11(3):283-294.
31. Shaw JP, Louie MS, Krishnamurthy VV, Arimilli MN, Jones RJ, Bidgood AM, Lee WA, Cundy KC: Pharmacokinetics and metabolism of selected prodrugs of PMEA in rats. Drug Metab Dispos (1997) 25(3):362-366.
32. Van Gelder J, Deferme S, Annaert P, Naesens L, De Clercq E, Van den Mooter G, Kinget R, Augustijns P: Increased absorption of the antiviral ester prodrug tenofovir disoproxil in rat ileum by inhibiting its intestinal metabolism. Drug Metab Dispos (2000) 28(12):1394-1396.
33. van Poelje PD, Potter SC, Chandramouli VC, Landau BR, Dang Q, Erion MD: Inhibition of fructose 1,6-bisphosphatase reduces excessive endogenous glucose production and attenuates hyperglycemia in Zucker diabetic fatty rats. Diabetes (2006) 55(6):1747-1754. • Provides the first account of the effects of chronic inhibition of FBPase in animal models of diabetes.
34. Erion MD, Potter SC, van Poelje PD: Fructose 1,6-bisphosphatase inhibition improves oral glucose tolerance and enhances the antidiabetic action of glyburide in the Zucker diabetic fatty rat. Diabetologia (2004) 47(Suppl 1):Abs 0796.
35. van Poelje PD, Potter SC, Topczewski E, Hou J, Linemeyer DL, Erion MD: Combination therapy with pioglitazone and a fructose-1,6-bisphosphatase inhibitor (MB06322) improves glycemic control and lactate homeostasis in male Zucker diabetic fatty (ZDF) rats. Diabetologia (2006) 49(Suppl 1):Abs 0852.
36. Walker J, Triscari J, Dmuchowski C, Kaneko T, Bruce SR: Safety and tolerability of single doses of CS-917, a novel gluconeogenesis inhibitor, in normal male volunteers. Diabetes (2006) 5 (Suppl 1):Abs 2002-PO.
37. Walker J, Triscari J, Dmuchowski C, Kaneko T, Bruce SR: Safety, tolerability and pharmacodynamics of multiple doses of CS-917 in normal volunteers. Diabetes (2006) 55(Suppl 1):Abs 2003-PO.
38. Triscari J, Walker J, Feins K, Tao B, Bruce SR: Multiple ascending doses of CS-917, a novel fructose 1,6-bisphosphatase (FBPase) inhibitor, in subjects with type 2 diabetes treated for 14 days. Diabetes (2006) 55(Suppl 1):Abs 444-P. • Describes the first multi-day clinical studies of an FBPase inhibitor in patients with type 2 diabetes.
39. Bruce SR, Walker J, Feins K, Tao B, Triscari J: Initial safety, tolerability and glucose lowering of CS-917, a novel fructose 1,6-bisphosphatase (FBPase) inhibitor, in subjects with type 2 diabetes. Diabetologia (2006) 49(Suppl 1):Abs 0037.
40. GENSIA PHARMACEUTICALS INC (Ugarkar BG, Tuttle RR, Metzner EK, Marangos PJ, Browne CE, Reich JW, Gruber HE): Administration of fructose-1,6-diphosphatase inhibitor - to lower blood glucose levels, inhibit gluconeogenesis and treat diabetes. US-05658889 (1994).
41. MERCK GMBH (Moinet G, Botton G, Arbellot de Vacquer A): Novel imidazolecarboxamide derivatives as fructose-1,6-bisphosphatase inhibitors, and pharmaceutical compositions comprising same. WO-2007014619 (2007).
42. METABASIS THERAPEUTICS INC (Reddy KR, Scarlato GR, Dang Q, Erion MD, Kasibhatla SR, Reddy MR): Indole and azaindole inhibitors of fructose-1,6-bisphosphatase. WO-09839342 (1998).
43. METABASIS THERAPEUTICS INC (Dang Q, Erion MD, Reddy MR, Robinson ED, Kasibhatla SR, Reddy KR): Novel purine inhibitors of fructose-1,6-bisphosphatase. WO-09839344 (1998).
44. METABASIS THERAPEUTICS INC (Kasibhatla SR, Reddy KR, Erion MD, Dang Q, Scarlato GR, Reddy MR): Novel benzimidazole inhibitors of fructose-1,6-bisphosphatase. WO-09839343 (1998).
45. METABASIS THERAPEUTICS INC (Bookser BC, Dang Q, Reddy KR): Novel aryl fructose-1,6-bisphosphatase inhibitors useful for treating diabetes. WO-00166553 (2001).
46. METABASIS THERAPEUTICS INC (Dang Q, Kasibhatla SR, Reddy KR, Erion MD, Reddy MR, Agarwal A): Novel heteroaromatic inhibitors of fructose-1,6-bisphosphatase. WO-00014095 (2000). • Discloses MB05032 (the active metabolite of CS-917) and other FBPase inhibitors of the thiazole class.
47. METABASIS THERAPEUTICS INC (Jiang T, Kasibhatla SR, Reddy KR): Novel bisamidate phosphonate prodrugs. WO-00147935 (2001). • Discloses a novel diamide prodrug class with utility for the oral delivery of molecules with phosphonic acid functionality.
48. METABASIS THERAPEUTICS INC (van Poelje PD, Erion MD, Fujiwara T): Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes. WO-00203978 (2002).
49. METABASIS THERAPEUTICS INC (van Poelje PD, Erion MD): Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes. WO-00038666 (2000).