Chapter 4
Discovery of Heterocyclic Phosphonic Acids as Novelampmimics that are Potent and Selective Fructose-1,6-Bisphosphatase Inhibitors and Elicit Potent Glucose-Lowering Effects in Diabetic Animals and Humans
Qun Dang,
Mark D. Erion,
Qun Dang
Departments of Medicinal Chemistry and Biochemistry, Metabasis Therapeutics, Inc. La Jolla, CA, USA
Search for more papers by this authorMark D. Erion
Metabasis Therapeutics, Inc., Departments of Medicinal Chemistry and Biochemistry, La Jolla, CA, USA
Search for more papers by this authorQun Dang,
Mark D. Erion,
Qun Dang
Departments of Medicinal Chemistry and Biochemistry, Metabasis Therapeutics, Inc. La Jolla, CA, USA
Search for more papers by this authorMark D. Erion
Metabasis Therapeutics, Inc., Departments of Medicinal Chemistry and Biochemistry, La Jolla, CA, USA
Search for more papers by this authorBook Editor(s):Xianhai Huang, Robert G. Aslanian,
Summary
This chapter contains sections titled:
-
Introduction
-
The Discovery of MB06322
-
Pharmacokinetic Studies of MB06322
-
Synthetic Routes to MB06322
-
Clinical Studies of MB06322
-
Summary
-
References
REFERENCES
- SMUSHKIN, G. and VELLA, A. What is type 2 diabetes? Medicine (Baltimore), 2010, 38, 597–601.
- DEFRONZO, R. A., FERRANNINI, E., and SIMONSON, D. C. Type 2 diabetes mellitus: epidemiology. Metabolism 1989, 38, 387–395.
- JENG, C. Y., SHEU, W. H., FUH, M. M., CHEN, Y. D., and REAVEN, G. M. Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM. Diabetes 1994, 43, 1440–1444.
- PERRIELLO, G., PAMPANELLI, S., DEL SINDACO, P., LALLI, C., CIOFETTA, M., VOLPI, E., SANTEUSANIO, F., BRUNETTI, P., and BOLLI, G. B. Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM. Diabetes 1997, 46, 1010–1016.
- MAGNUSSON, I., ROTHMAN, D. L., KATZ, L. D., SHULMAN, R. G., and SHULMAN, G. I. increased rate of gluconeogenesis in type 11 diabetes mellitus. A 13C nuclear magnetic resonance study. J. Clin. Invest. 1992, 90, 1323–1327.
- DAVIS, S. N. The role of glimepiride in the effective management of type 2 diabetes. J. Diabetes Complications 2004, 18, 367–376.
- GILLIES, P.S. and DUNN, C. J. Pioglitazone. Drugs 2000, 60, 333-343; discussion 344–345.
- HUNDAL, R. S., KRSSAK, M., DUFOUR, S., LAURENT, D., LEBON, V., CHANDRAMOULI, V., INZUCCHI, S. E., SCHUMANN, W. C., PETERSEN, K. F., LANDAU, B. R., and SHULMAN, G.I. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000, 49, 2063–2069.
- THORNBERRY, N. A. and WEBER, A. E. Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Curr. Top. Med. Chem. 2007, 7, 557–568.
- EL-MAGHRABI, M. R., GIDH-JAIN, M., AUSTIN, L. R., and PILKIS, S. J. Isolation of a human fructose-1, 6-bisphosphatase cDNA and expression of the protein in Escherichia coli. J. Biol. Chem. 1993, 268, 9466–9472.
- STEINMANN, B., VAN DEN BERGH, S. G., GITZELMANN, R. Disorders of fructose metabolism. The Metabolic and Molecular Bases of Inherited Disease, seventh edition, Vol 1 (eds C.R. SCRIVER, A. L. BEAUDET, W. S. SLY, and D. VALLE), McGraw-Hill, New York, 1995, p. 905.
- PILKIS, S. J. and CLAUS, T. H. Hepatic gluconeogenesis/glycolysis: regulation and structure/function relationships of substrate cycle enzymes. Annu. Rev. Nutr. 1991, 11, 465–515.
- KE, H. M., LIANG, J. Y., ZHANG, Y. P., and LIPSCOMB, W.N. 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, 4412–4420.
- MARYANOFF, B. E., REITZ, A. B., TUTWILER, G. F., BENKOVIC, S. J., BENKOVIC, P. A., and PILKIS, S. J. Stereoselective synthesis and biological activity of beta- and alpha-D-arabinose 1, 5-diphosphate: analogs of a potent metabolic regulator. J. Am. Chem. Soc. 1984, 106, 7851–7853.
- WRIGHT, S. W., CARLO, A. A., CARTY, M. D., DANLEY, D. E., HAGEMAN, D. L., KARAM, G. A., LEVY, C. B., MANSOUR, M. N., MATHIOWETZ, A. M., MCCLURE, L. D., NESTOR, N. B., MCPHERSON, R. K., PANDIT, J., PUSTILNIK, L. R., SCHULTE, G. K., SOELLER, W. C., TREADWAY, J. L., WANG, I. K., and BAUER, P. H. 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, 3865–3877.
- WRIGHT, S. W., CARLO, A. A., DANLEY, D. E., HAGEMAN, D. L., KARAM, G. A., MANSOUR, M. N., MCCLURE, L. D., PANDIT, J., SCHULTE, G. K., TREADWAY, J. L., WANG, I. K., and BAUER, P. H. 3-(2-carboxyethyl)-4, 6-dichloro-1Hindole-2-carboxylic acid: an allosteric inhibitor of fructose-1, 6-bisphosphatase at the AMP site. Bioorg. Med. Chem. Lett. 2003, 13, 2055–2058.
- CHOE, J. Y., NELSON, S. W., ARIENTI, K. L., AXE, F.U., COLLINS, T. L., JONES, T. K., KIMMICH, R. D., NEWMAN, M. J., NORVELL, K., RIPKA, W. C., ROMANO, S. J., SHORT, K. M., SLEE, D. H., FROMM, H. J., and HONZATKO, R.B. Inhibition of fructose-1, 6-bisphosphatase by a new class of allosteric effectors. J. Biol. Chem. 2003, 278, 51176–51183.
- LAI, C., GUM, R. J., DALY, M., FRY, E. H., HUTCHINS, C., ABAD-ZAPATERO, C., and VON GELDERN, T.W. Benzoxazole benzenesulfonamides as allosteric inhibitors of fructose-1, 6-bisphosphatase. Bioorg. Med. Chem. Lett. 2006, 16, 1807–1810.
- VON GELDERN, T. W., LAI, C., GUM, R. J., DALY, M., SUN, C., FRY, E. H., and ABAD-ZAPATERO, C. Benzoxazole benzenesulfonamides are novel allosteric inhibitors of fructose-1, 6-bisphosphatase with a distinct binding mode. Bioorg. Med. Chem. Lett. 2006, 16, 1811–1815.
- SHAIKH, M. S., MITTAL, A., and BHARATAM, P. V. Design of fructose-2, 6-bisphosphatase inhibitors: a novel virtual screening approach. J. Mol. Graph. Model 2008, 26, 900–906.
- TSUKADA, T., KANNO, O., YAMANE, T., TANAKA, J., YOSHIDA, T., OKUNO, A., SHIIKI, T., TAKAHASHI, M., and NISHI, T. Discovery of potent and orally active tricyclic-based FBPase inhibitors. Bioorg. Med. Chem. 2008, 18, 5346–5351.
- HENG, S., GRYNCEL, K. R., and KANTROWITZ, E.R. A library of novel allosteric inhibitors against fructose 1, 6-bisphosphatase. Bioorg. Med. Chem, 2009, 17, 3916–3922.
- RUDNITSKAYA, A., HUYNH, K., TOROK, B., and STIEGLITZ, K. Novel heteroaromatic organofluorine inhibitors of fructose-1, 6-bisphosphatase. J. Med. Chem. 2009, 52, 878–882.
- HENG, S., HARRIS, K. M., and KANTROWITZ, E.R. Designing inhibitors against fructose 1, 6-bisphosphatase: exploring natural products for novel inhibitor scaffolds. Eur, J. Med. Chem. 2010, 45, 1478–1484.
- KITAS, E., MOHR, P., KUHN, B., HEBEISEN, P., WESSEL, H.P., HAAP, W., RUF, A., BENZ, J., JOSEPH, C., HUBER, W., SANCHEZ, R. A., PAEHLER, A., BENARDEAU, A., GUBLER, M., SCHOTT, B., and TOZZO, E. Sulfonylureido thiazoles as fructose-1, 6-bisphosphatase inhibitors for the treatment of type-2 diabetes. Bioorg. Med. Chem. Lett. 2010, 20, 594–599.
- RUDNITSKAYA, A., BORKIN, D. A., HUYNH, K., TOROK, B., and STIEGLITZ, K. Rational design, synthesis, and potency of N-substituted indoles, pyrroles, and triarylpyrazoles as potential fructose 1, 6-bisphosphatase inhibitors. Chem. Med. Chem. 2010, 5, 384–389.
- ERION, M. D., VAN POELJE, P. D., DANG, Q., KASIBHATLA, S. R., POTTER, S. C., REDDY, M. R., REDDY, K. R., JIANG, T., and LIPSCOMB, W. N. 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, 7970–7975.
- WANG, Y., and TOMLINSON, B. Managlinat dialanetil, a fructose-1, 6-bisphosphatase inhibitor for the treatment of type 2 diabetes. Curr. Opin. Investig. Drugs 2007, 8, 849–858.
- TRISCARI, J., WALKER, J., FEINS, K., TAO, B., and BRUCE, S. R. A novel fructose-1, 6-bisphosphatase (FBPase) inhibitor. Subjects with Type 2 Diabetes Treated for 14 Days. The American Diabetes Association 66th Scientific Session, Washington, DC, 2006.
- DANG, Q., BROWN, B. S., LIU, Y., RYDZEWSKI, R. M., ROBINSON, E. D., VAN POELJE, P. D., REDDY, M. R., and ERION, M. D. Fructose-1, 6-bisphosphatase inhibitors: 1. Purine phosphonic acids as novel AMP mimics. J. Med. Chem. 2009, 52, 2880–2898.
- GIDH-JAIN, M., ZHANG, Y., VAN POELJE, P. D., LIANG, J.Y., HUANG, S., KIM, J., ELLIOTT, J. T., ERION, M. D., PILKIS, S. J., and RAAFAT EL-MAGHRABI, M. 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, 27732–27738.
- DANG, Q. Organophosphonic acids as drug candidates. Exp. Opin. Therapeutic Patents 2006, 16, 343.
- REDDY, M. R.; ERION, M.D. J. Am. Chem. Soc. 2007, 129, 9296–9297.
- ERION, M.D.; DANG, Q.; REDDY, M.R.; KASIBHATLA, S. R.; HUANG, J.; LIPSCOMB, W.N.; VAN POELJE, P. D. Structure-Guided Design of AMP Mimics that Inhibit Fructose 1, 6-Bisphosphatase with High Affinity and Specificity. J. Am. Chem. Soc. 2007, 129, 15480–15490.
- ERION, M. D.; SRINIVAS, R. K.; BOOKSER, B. C.; VAN POELJE, P. D.; REDDY, M. R.; GRUBER, H. E.; APPLEMAN, J. R. J. Am. Chem. Soc. 1999, 121, 308–319.
- DANG, Q., KASIBHATLA, S. R., XIAO, W., LIU, Y., DARE, J., TAPLIN, F., REDDY, K. R., SCARLATO, G. R., GIBSON, T., VAN POELJE, P. D., POTTER, S. C., and ERION, M. D. Fructose-1, 6-bisphosphatase inhibitors: 2. Design, synthesis, and structure–activity relationship of a series of phosphonic acid containing benzimidazoles that function as 50-adenosinemonophosphate (AMP) mimics. J. Med. Chem. 2010, 53, 441–451.
- SUN, W., WU, R. R., VAN POELJE, P. D., and ERION, M.D. Isolation of a family of organic anion transporters from human liver and kidney. Biochem. Biophys. Res. Commun. 2001, 283, 417–422.
- DANG, Q., LIU, Y., CASHION, D.K., KASIBHATLA, S. R., JIANG, T., TAPLIN, F., JACINTHO, J. D., LI, H., SUN, Z., FAN, Y., DARE, J., TIAN, F., LI, W., GIBSON, T., LEMUS, R., VAN POELJE, P.D., POTTER, S.C., and ERION, M. D. Discovery of a series of phosphonic acid-containing thiazoles and orally bioavailable diamide prodrugs that lower glucose in diabetic animals through inhibition of fructose-1, 6-bisphosphatase. J. Med. Chem. 2011, 54, 153–165.
- KRISE, J. P. and STELLA, V. J. Prodrugs of phosphates, phosphonates, and phosphinate. Adv. Drug Deliv. Rev. 1996, 19, 287–310.
- HECKER, S.J. and ERION, M. D. Prodrugs of phosphates and phosphonates. J. Med. Chem. 2008, 51, 2328–2345.
- DANG, Q., KASIBHATLA, S.R., JIANG, T., FAN, K., LIU, Y., TAPLIN, F., SCHULZ, W., CASHION, D.K., REDDY, K. R., VAN POELJE, P.D., FUJITAKI, J.M., POTTER, S.C., and ERION, M. D. Discovery of phosphonic diamide prodrugs and their use for the oral delivery of a series of fructose 1, 6-bisphosphatase inhibitors. J. Med. Chem. 2008, 51, 4331–4339.
- MCGUIGAN, C. M., HARRIS, S. A., DALUGE, S. M., GUDMUNDSSON, K. S., MCLEAN, E. W., BURNETTE, T.C., MARR, H., HAZEN, R., CONDREAY, L. D., JOHNSON, L., DE CLERCQ, E., and BALZARINI, J. Application of Phosphoramidate Pronucleotide Technology to Abacavir Leads to a Significant Enhancement of Antiviral Potency. J. Med. Chem. 2005, 48, 3504–3515.
- DANG, Q., KASIBHATLA, S.R., REDDY, K.R., JIANG, T., REDDY, M. R., POTTER, S.C., FUJITAKI, J.M., VAN POELJE, P.D., HUANG, J., LIPSCOMB, W.N., and ERION, M.D. Discovery of potent and specific fructose-1, 6-bisphosphatase inhibitors and a series of orally-bioavailable phosphoramidase-sensitive prodrugs for the treatment of type 2 diabetes. J. Am. Chem. Soc. 2007, 129, 15491–15502.
-
VAN POELJE, P. D.; DANG, Q.; ERION, M. D. Fructose 1, 6-bisphosphatase as a therapeutic target for type 2 diabetes. Drug Discovery Today: Ther. Strategies 2007, 4, 103–109.
10.1016/j.ddstr.2007.10.003 Google Scholar
- VAN POELJE, P. D.; DANG, Q.; ERION, M. D. Discovery of fructose 1, 6-bisphosphatase inhibitors for the treatment of type 2 diabetes. Curr. Opin. Drug Discovery Dev. 2007, 10, 430–437.
- VAN POELJE, P.D.; POTTER, S. C.; CHANDRAMOULI, V. C.; LANDAU, B. R.; DANG, Q.; ERION, M. D. Inhibition of fructose 1, 6-bisphosphatase reduces excessive endogenous glucose production and attenuates hyperglycemia in zucker diabetic Fatty rats. Diabetes 2006, 55, 1747–1754.
