A survey of small molecule glucagon receptor antagonists from recent patents (2006-2010)

Expert Opinion on Therapeutic Patents

Volumn 21, Issue 8, 2011, Pages 1211-1240

  Shen, Dong Ming ^a   Lin, Songnian ^a   Parmee, Emma R ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

glucagon; glucagon receptor; glucagon receptor antagonists; type 2 diabetes mellitus

Indexed keywords

GLUCAGON RECEPTOR; GLUCAGON RECEPTOR ANTAGONIST; HORMONE RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG;

DRUG RECEPTOR BINDING; DRUG RESEARCH; DRUG STRUCTURE; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATENT; RECEPTOR BLOCKING; REVIEW;

ANIMALS; DIABETES MELLITUS, TYPE 2; HUMANS; HYPOGLYCEMIC AGENTS; PATENTS AS TOPIC; RECEPTORS, GLUCAGON; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79960667427     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2011.587001     Document Type: Review

References (98)

1. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813-20 (Pubitemid 34000785)
2. Aronson D. Hyperglycemia and the pathobiology of diabetic complications. Adv in Cardiology 2008;4:1-16
3. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics, 2007 fact sheet. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, 2008. Available from: . niddk.nih.gov/dm/pubs/statistics/ [Last accessed 11 December 2010]
4. Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010;362:1090-101
5. Wild S, Sicree R, Roglic G, et al. Global prevalence of diabetes, estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-53 (Pubitemid 38579764)
6. Chao EC, Henry RR. SGLT2 inhibition-a novel strategy for diabetes treatment. Nature Rev Drug Disc 2010;9:551-9
7. Carpino PA, Goodwin B. Diabetes area participation analysis: a review of companies and targets described in the 2008 - 2010 patent literature. Expert Opin Ther Patents 2010;20:1627-51
8. Petersen KF, Sullivan JT. Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia 2001;44:2018-24 (Pubitemid 33124047)
9. Novo Nordisk A/S. Investor presentations March 2005 at SG Cowan & Co. 25th Annual Health Care Conference Boston; 15 March 2005. Available from: http://novonordisk.com/images/investors/investor-presentations/2005/ SG%20Cowen%20CKA03082005.ppt [Last accessed 19 January 2011]
10. Sloop KW, Michael MD. Role of the glucagon receptor in glucose homeostasis: a therapeutic target to improve glycemic control in type 2 diabetes. Drugs of the Future 2004;29:835-41 (Pubitemid 39403080)
11. Sloop KW, Michael MD, Moyers JS. Glucagon as a target for the treatment of type 2 diabetes. Expert Opin Ther Targets 2005;9:593-600 (Pubitemid 40883156)
12. Connell RD. Glucagon antagonists for the treatment of type 2 diabetes. Expert Opin Ther Patents 1999;9:701-9 (Pubitemid 29259657)
13. Ling AL, Wasserman JI. Approaches to glucagon receptor antagonists. Expert Opin Ther Patents 2003;13:15-22 (Pubitemid 36113796)
14. Kurukulasuriya R, Link JT. Progress towards glucagon receptor antagonist therapy for type 2 diabetes. Expert Opin Ther Patents 2005;15:1739-49 (Pubitemid 43056411)
15. DeMong DE, Miller MW, Lachowicz JE. Glucagon receptor antagonists, Chapter 8 Ann Rep in Med Chem 2008;43:119-137
16. Conarello SL, Jiang G, Mu J, et al. Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozocin-mediated beta cell loss and hyperglycaemia. Diabetologia 2007;40:142-50 (Pubitemid 46035862)
17. Novo Nordisk A/S & Agouron Pharmceutical, Inc. Glucagon antagonists/inverse agonists. WO 200069810; 2000 and US 6,503,949; 2003
18. Merck & Co., Inc. Substituted pyridyl pyrroles, compositions containing such compounds and methods of use. WO199716442; 1997
19. Merck & Co., Inc. Triaryl substituted imidazoles and methods of use. WO199822108; 1998
20. Merck & Co., Inc. Method of treating diabetes and related conditions. WO2004024066; 2004
21. Merck & Co., Inc. Cyanothiophene derivatives, compositions containing such compounds and methods of use. US20040097552; 2004
22. Merck & Co., Inc. Cyanothiophene derivatives, compositions containing such compounds and methods of use. US20040097557; 2004
23. Merck & Co., Inc. Spirocyclic ureas, compositions containing such compounds and methods of use. WO2004050039; 2004
24. Shen D-M, Zhang F, Brady EJ, et al. Discovery of novel, potent and orally active spiro-urea human glucagon receptor antagonists. Bioorg Med Chem Lett 2005;15:4564-9 (Pubitemid 41253896)
25. Merck & Co., Inc. Benzimidazoles, compositions containing such compounds and methods of use. WO2004100875; 2004
26. Kim RM, Chang J, Lins AR, et al. Discovery of potent, orally active benzimidazole glucagon receptor antagonists. Bioorg Med Chem Lett 2008;18:3701-5
27. Merck & Co., Inc. Cyclic guanidines, compositions containing such compounds and methods of use. WO2005065680; 2005
28. Merck & Co., Inc. Merck & Co., Inc. Substituted pyrazoles, compositions containing such compounds and methods of use. WO2004069158; 2004
29. Merck & Co., Inc. Pyrazole derivatives, compositions containing such compounds and methods of use. US20050272794; 2005
30. Shen D-M, Brady EJ, Candelore MR, et al. Discovery of novel human glucagon receptor antagonists containing a pyrazole core. Bioorg Med Chem Lett 2011;21:76-81
31. Merck & Co., Inc. Process for synthesizing a substituted pyrazole. WO2007015999; 2007
32. Merck & Co., Inc. Process for the production of a crystalline glucagonreceptor antagonist compound. WO2009035558; 2009
33. Merck & Co., Inc. Substituted pyrazoles, compositions containing such compounds and methods of use. WO2006014618; 2006
34. Merck & Co., Inc. Pyrazole amide derivatives, compositions containing such compounds and methods of use. WO2006017055; 2006
35. Merck & Co., Inc. Substituted aryl and heteroaryl derivatives. WO2006102067; 2006
36. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2006104826; 2006
37. Liang R, Abrardo L, Brady EJ, et al. Design and synthesis of conformationally constrained tri-substituted ureas as potent antagonists of the human glucagon receptor. Bioorg Med Chem Lett 2007;17:587-92 (Pubitemid 46108581)
38. Shiao L-L, Cascieri MA, Trumbauer M, et al. Generation of mice expressing the human glucagon receptor with a direct replacement vector. Transgenic Res 1999;8:295-302 (Pubitemid 29523967)
39. Dallas-Yang Q, Shen X, Strowski M, et al. Hepatic glucagon receptor binding and glucose-lowering in vivo by peptityl and non-peptidyl glucagon receptor antagonists. Eur J Pharmacol 2004;501:225-34 (Pubitemid 39298956)
40. Merck & Co., Inc. Acyl indoles, compositions containing such compounds and methods of use. WO2007047177; 2007
41. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2007111864; 2007
42. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of useWO2007136577; 2007
43. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2008042223; 2008
44. Merck & Co., Inc. Crystalline polymorphic forms of an antidiabetic compound. WO2010080971; 2010
45. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2010030722; 2010
46. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2010071750; 2010
47. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2010088061; 2010
48. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2010098994; 2010
49. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2010093535; 2010
50. Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use. WO2010098948; 2010
51. Eli Lilly and Co. Glucagon receptor antagonists. WO2009120530; 2009
52. Eli Lilly and Co. Glucagon receptor antagonists, preparation and therapeutic uses. WO2005118542; 2005
53. Eli Lilly and Co. Glucagon receptor antagonists, preparation and therapeutic uses. WO2005123668; 2005
54. Eli Lilly and Co. Glucagon receptor antagonists, preparation and therapeutic uses. WO2006086488; 2006
55. Eli Lilly and Co. Glucagon receptor antagonists, preparation and therapeutic uses. WO2007106181; 2007
56. Eli Lilly and Co. Glucagon receptor antagonists, preparation and therapeutic uses. WO2007114855; 2007
57. Eli Lilly and Co. Glucagon receptor antagonists, preparation and therapeutic uses. WO2007123581; 2007
58. Eli Lilly and Co. Glucagon receptor antagonists, preparation and therapeutic uses. WO2007120270; 2007
59. Eli Lilly and Co. Glucagon receptor antagonists, preparation and therapeutic uses. WO2007120284; 2007
60. Schering Corp. Glucagon receptor antagonists, compositions, and method for their use. WO09140342; 2009
61. Schering Corp. Thiophenes as glucagon receptor antagonists, compositions, and methods for their use. WO2010144664; 2010
62. Schering Corp. Spiro-imidazolone derivatives as glucagon receptor antagonists. WO2010039789; 2010
63. After this review was submitted, three presentations on imidazolone series of glucagon receptor antagonist have appeared which identified compound 59 as SCH900822 at the 241st National Meeting of the American Chemical Society, Anaheim, CA. 27-31 March 2011: a) Dai X, DeMong DE, Miller MW, et al. Discovery of a highly potent and selective imidazolone-based glucagon receptor antagonist.; b) DeMong DE, Dai X, Miller MW, et al. Imidazolone-based glucagon receptor antagonists: Lead identification; c) DeMong DE, Miller MW, Lin S-I, et al. Development of a novel and expedient synthesis of 4-arylimidazolones 64. Ligand completes acquisition of Metabasis. Ligand Pharmaceuticals, Inc., 2010. Available from: . ligand.com/releasedetail.cfm? ReleaseID=441087 [Last accessed 18 December 2010]
64. Metabasis Therapeutics, Inc. Novel antagonists of the glucagon receptor. WO2008098244; 2008
65. Metabasis Therapeutics, Inc. Glucagon antagonists. WO2010019830; 2010
66. Metabasis Therapeutics, Inc. Glucagon receptor antagonists. WO2010019828; 2010
67. Takeda Pharmaceutical Co. Ltd. Heterocyclic compound. WO2009057784; 2009. See also EP2210876; 2010 and US2010256156; 2010
68. Takeda Pharmaceutical Co. Ltd. Heterocyclic compound. WO2009110520; 2009. See also EP2251326; 2010
69. Lau J, Behrens C, Sidelmann UG, et al. New beta-alanine derivatives are orally available glucagon receptor antagonists. J Med Chem 2007;50:113-28 (Pubitemid 46105504)
70. Kodra JT, Thøgersen AS, Andersen, B, et al. Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insolnotropic polypeptide receptor. J Med Chem 2008;51:5387-96
71. Novo Nordisk A/S. Glucagon antagonists/inverse agonists. WO200200612; 2002
72. Rivera N, Everett-Grueter CA, Edgerton SD, et al. A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog. J Pharmacol Exp Ther 2007;321:743-52 (Pubitemid 46624501)
73. Lue B-M, Nielsen FS, Magnussen T, et al. Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound. Eur J Pharm Biopharm 2008;69:648-57
74. Madsen P, Kodra JT, Behrens C, et al. Human glucagon receptor antagonists with thiazole cores: a novel series with superior pharmacokinetic properties. J Med Chem 2009;52:2898-3000
75. Novo Nordisk A/S. Novel glucagon antagonists/inverse agonists. WO2004002480; 2004
76. Dainippon Sumitomo Pharma Co., Ltd. 3-(4-Aminophenyl)-2-furancarboxylic acid derivative and pharmaceutically acceptable salt thereof. WO2010131669; 2010
77. Ling A, Hong Y, Gonzalez J, et al. Identification of alkylidene hydrazides as glucagon receptor antagonists. J Med Chem 2001;44:3141-9 (Pubitemid 32862345)
78. Ling A, Plewe M, Gonzalez J, et al. Human glucagon receptor antagonists based on alkylidene hydrazides. Bioorg Med Chem Lett 2002;12:663-6 (Pubitemid 34158917)
79. Novo Nordisk A/S & Agouron Pharmaceutical, Inc.: Glucagon antagonists/inverse agonists. WO199901423; 1999
80. Novo Nordisk A/S & Agouron Pharmaceutical, Inc.: Glucagon antagonists/inverse agonists. WO200039088; 2000
81. Dainippon Sumitomo Pharma Co., Ltd. 3-Substituted-2-furancarboxylic acid derivative and pharmaceutically acceptable salt thereof. WO2011007722; 2011
82. Boehringer Ingelheim International GMBH. Cyanothiophenes, the production thereof and their use as medicaments. WO2006042850; 2006
83. Duffy JL, Kirk BA, Konteatis Z, et al. Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor. Bioorg Med Chem Lett 2005;15:1401-5 (Pubitemid 40269001)
84. Madsen P, Ling, A, et al. Optimization of alkylidene hydrazide based human glucagon receptor antagonist. Discovery of the highly potent and orally available 3-cycno-4-hydroxybenoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol- 4-ylmethylene]hydrazide. J Med Chem 2002;4:755-5775
85. Albert JS, Hoboken NJ. Fragment-based lead discovery in Lead generation approaches in drug discovery. John Wiley 2010;105-139
86. Yanamala N, Dutta A, Beck B, et al. NMR-based screening of membrane protein ligands Chem Biol Drug Des 2010;75:237-56
87. PRNewswire, BAGSVAERD, Denmark, April 28 /PRNewswire-FirstCall/ - Financial statement for the period 1 January 2005 to 31 March 2005. Available from: http://www2.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/=www/ story/04-28-2005/0003491089&EDATE= [Last accessed 19 January 2011]
88. Ouyang D, Dhall D, Yu R. alpha Cell hyperplasia is a very rare conditioin. For a recent review see Pathological pancreatic endocrine cell hyperplasia. World J Gastroenterol 2011;17:137-43
89. Zhou C, Dhall D, Nissen NN, et al. Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonenia, alpha cell hyperplasia, and islet cell tumor. Pancreas 2009;38:941-6
90. Gelling RW, Du XQ, Dichmann DS, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. PNAS 2003;100:1438-43 (Pubitemid 36184020)
91. Sloop KW, Cao JX, Siesky AM, et al. Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest 2004;113:1571-81 (Pubitemid 39071680)
92. Gu W, Yan H, Winters KA, et al. Long-term inhibition of the glucagon receptor with a monoclonal antibody in mice causes sustained improvement in glycemic control, with reversible alpha-cell hyperplasia and hyperglucagonemia. J Pharmac Exp Therapeutics 2009;331:871-81
93. Kedees MH, Grigoryan M, Guz Y, Teitelman G. Differential expression of glucagon and glucagon-like peptide 1 receptors in mouse pancreatic alpha and beta cells in two models of alpha cell hyperplasia. Mol Cell Endocrinology 2009;311:69-76 and references cited therein
94. Winzell MS, Brand CL, Wierup N, et al. Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet. Biabetologia 2007;50:1453-62 (Pubitemid 46879005)
95. Mu J, Jiang G, Brady E, et al. Chronic treatment with a glucagon receptor antagonist lowers glucose and moderately raises circulating glucagon and glucagon-like peptide 1 without severe alpha cell hypertrophy in diet-induced obese mice. Diabetologia, [In press]
96. Cascieri MA, Koch GE, Ber E, et al. Characterization of a novel, non-peptidyl antagonist of the human glucagon receptor. J Biol Chem 1999;274:8694-7 (Pubitemid 29164665)
97. Hoare SRJ. Allosteric modulators of class B G-protein-coupled receptors. Cur Neuropharmacol 2007;5:168-79 (Pubitemid 351863858)
98. After this review was submitted, Merck has disclosed that compound 1 is MK-0893, its experimental glucagon receptor antagonist: Parmee ER. Discovery of MK-0893: A glucagon receptor antagonist for the treatment of type 2 diabetes. 241st National Meeting of the American Chemical Society, Anaheim, CA. 27-31 March 2011