Optimization of alkylidene hydrazide based human glucagon receptor antagonists. Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1h-indol-4ylmethylene]hydrazide

Journal of Medicinal Chemistry

Volumn 45, Issue 26, 2002, Pages 5755-5775

  Madsen, Peter ^a   Ling, Anthony ^b   Plewe, Michael ^b   Sams, Christian K ^a   Knudsen, Lotte B ^a   Sidelmann, Ulla G ^a   Ynddal, Lars ^a   Brand, Christian L ^a   Andersen, Birgitte ^a   Murphy, Douglas ^b   Teng, Min ^b   Truesdale, Larry ^b   Kiel, Dan ^b   May, John ^b   Kuki, Atsuo ^b   Shi, Shenghua ^b   Johnson, Michael D ^b   Teston, Kimberly Ann ^b   Feng, Jun ^b   Lakis, James ^b   Anderes, Kenna ^b   Gregor, Vlad ^b   Lau, Jesper ^a   more..

^a NOVO NORDISK A S   (Denmark)

^b PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 CYANO 4 HYDROXYBENZOIC ACID [1 (2,3,5,6 TETRAMETHYLBENZYL) 1H INDOL 4 YLMETHYLENE]HYDRAZIDE; BENZOIC ACID DERIVATIVE; GLUCAGON; GLUCAGON RECEPTOR; GLUCOSE; NNC 25 2504; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; COMPETITIVE INHIBITION; CONTROLLED STUDY; DNA LIBRARY; DOG; HYPERGLUCAGONEMIA; HYPERGLYCEMIA; LIPOPHILICITY; LIVER CELL; NONHUMAN; RECEPTOR BINDING; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CELLS, CULTURED; DOGS; GLUCAGON; GLUCOSE; HEPATOCYTES; HUMANS; HYDRAZINES; HYPERGLYCEMIA; INDOLES; MALE; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, GLUCAGON; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0037137607     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0208572     Document Type: Article

References (27)

1. Lok, S.; Kujiper, J. L.; Jelinek, L. J.; Kramer, J. M.; Whitmore, T. E.; Sprecher, C. A.; Methewes, S.; Grant, F. J.; Biggs, S. H.; Rosenberg, G. B. The human glucagon receptor encoding gene: Structure, cDNA sequence and chromosomal localization. Gene 1994, 140, 203-209.
2. Kindsvogel, W.; Jelinek, L. J.; Grant, F. J.; Kujper, J. L.; Foster, D. C.; Lok, S. U.S. Patent 5,770,445, 1998.
3. DeFronzo, R. A.; Bonadonna, R. C.; Ferrannini, E. Pathogenesis of NIDDM, a balanced overview. Diabetes Care 1992, 15, 318-368.
4. Consoli, A.; Nurjhan, N.; Capiani, F.; Gerich, J. Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 1989, 38, 550-557.
5. Unger, R. H.; Orci, L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1975, 1, 14-16.
6. Dobbs, R. E.; Sakurai, H.; Sasaki, H.; Faloona, G.; Valverde, I.; Baetens, D.; Orici, L.; Unger, R. Glucagon: Role in the hyperglycemia of diabetes mellitus. science 1975, 187, 544-547.
7. Gerich, J. E.; Lorenzi, M.; Bier, D. M.; Schneider, V.; Tsalikian, E.; Karam, J. H.; Forsham, P. H. Prevention of human diabetic ketoacidosis by somatostatin. N. Engl. J. Med. 1975, 292, 985-989.
8. Brand, C. L.; Rolin, B.; Jørgensen, P. N.; Svendsen, I.; Kristensen, J. S.; Holst, J. J. Immunoneutralisation of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia 1994, 37, 985-993.
9. Brand, C. L.; Jørgensen, P. N.; Knigge, U.; Warberg, J.; Svendsen, I.; Kristensen, J. S.; Holst, J. J. Role of glucagon in maintanence of euglycemia in fed and fasted rats. Am. J. Physiol. 1995, 32, E469-E477.
10. Brand, C. L.; Joergensen, P. N.; Svendsen, I.; Holst, J. J. Evidence for a major role for glucagon in regulation of plasma glucose in conscious, nondiabetic, and alloxan-induced diabetic rabbits. Diabetes 1996, 45, 1076-1083.
11. Brandt, C. L.; Hansen, B.; Gronemann, S.; Moysen, M.; Holst, J. J. Subchronic glucagon neutralisation improves diabetes in ob/ob mice. Diabetes 2000, 49 (S1), A81.
12. Hansen, L. H.; Larger, E.; Chaput, J.-C.; Vissuzaine, C.; Holst, J. J.; Madsen, O. D.; Yakushiji, F.; De Meyts, P.; Assan, R.; Nishimura, E. Identification of a glucagon receptor gene deletion mutation in a patient with hyperglucagonemia and pseudoadenomatous hyperplasia of pancreatic alpha-cells. Presented at the 81st Annual Meeting of the Endocrine Society, San Diego, CA, 1999; Paper P3-441.
13. Parker, J. C.; Andrews, K. M.; Allen, M. R.; Stock, J. L.; McNeish, J. D. Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem. Biophys. Res. Commun. 2002, 290, 839-843.
14. Madsen, P.; Brand, C. L.; Holst, J. J.; Knudsen, L. B. Advances in non-peptide glucagon receptor antagonists. Curr. Pharm. Des. 1999, 5, 683-691.
15. Connell, R. D. Glucagon antagonists for the treatment of type 2 diabetes. Expert Opin. Ther. Pat. 1999, 9, 701-709.
16. Livingston, J. N. Glucagon and glucagon-like peptide-1. Annu. Rep. Med. Chem. 1999, 34, 189-198.
17. Chang, L. L.; Sidler, K. L.; Cascieri, M. A.; de Laszlo, S.; Koch, G.; Li, B.; MacCoss, M.; Mantlo, N.; O'Keefe, S.; Pang, M.; Rolando, A.; Hagmann, W. K. Substituted imidazoles as glucagon receptor antagonists. Bioorg. Med. Chem. Lett. 2001, 11, 2549-2553.
18. Ling, A.; Hong, Y.; Gonzalez, J.; Gregor, V.; Polinsky, A.; Kuki, A.; Shi, S.; Teston, K.; Porter, J.; Kiel, D.; Lakis, J.; Anderes, K.; May, J.; Knudsen, L. B.; Lau, J. Identification of alkylidene hydrazides as glucagon receptor antagonist. J. Med. Chem. 2001, 44, 3141-3149.
19. Ling, A.; Plewe, M. B.; Gonzalez, J.; Madsen, P.; Sams, C. K.; Lau, J.; Gregor, V.; Murphy, D.; Teston, K.; Kuki, A.; Shi, S.; Truesdale, L. K.; Kiel, D.; May, J.; Lakis, J.; Anderes, K.; Iatsimirskaia, E.; Sidelmann, U. G.; Knudsen, L. B.; Brand, C. L.; Polinsky, A. human glucagon receptor antagonists based on alkylidene hydrazides. Bioorg. Med. Chem. Lett. 2002, 12, 663-666.
20. Madsen, P.; Knudsen, L. B.; Wiberg, F. C.; Carr, R. D. Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists. J. Med. Chem. 1998, 41, 5150-5157.
21. Andersen, B.; Rassov, A.; Westergaard, N.; Lundgren, K. Inhibition of glycogenolysis in primary rat hepatocytes by 1,4-dideoxy1,4-imino-D-arabinitol. Biochem. J. 1999, 342, 545-550.
22. Kenakin, T. Pharmacological analysis of drug - receptor interaction, 3rd Ed.; Lippincott-Raven Publishers: Philadelphia, PA, 1997.
23. Knudsen, L. B.; Brand, C. L.; Sidelmann, U. G.; Teston, K; Ling, A.; Madsen, P.; Lau, J. NNC 25-2504, a potent glucagon receptor antagonist. Diabetes 2001, 50 (Suppl. 2), A309.
24. Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic technique for preparative separations with moderate resolution. J. Org. Chem. 1978, 43, 2923-2925.
25. Ling, A.; Gregor, V.; Gonzalez, J.; Hong, Y.; Kiel, D.; Kuki, A.; Shi, S.; Naerum, L.; Madsen, P.; Sams, C. K.; Lau, J.; Plewe, M. B.; Feng, J.; Teng, M.; Johnson, M. D.; Teston, K. A.; Sidelmann, U. G. Patent WO 99/01423, 1999.
26. Ling, A.; Kuki, A.; Shi, S.; Plewe, M. B.; Feng, J.; Truesdale, L. K.; May, J.; Kiel, D.; Madsen, P.; Sams, C. K; Lau, J. Patent WO 00/39088, 2000.
27. Shulezhko, A. A.; Kiprianov, A. I. Cyanine dyes with benzene, naphthalene and anthracene rings in the polymethine chain. J. Org. Chem. (USSR) Engl. Transl. 1968, 4, 1052-1055.