Calcitonin gene-related peptide receptor antagonists: New therapeutic agents for migraine

Journal of Medicinal Chemistry

Volumn 57, Issue 19, 2014, Pages 7838-7858

  Bell, Ian M ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA CALCITONIN GENE RELATED PEPTIDE; ANTIMIGRAINE AGENT; AZEPINE DERIVATIVE; BENZOTHIOPHENE DERIVATIVE; BETA CALCITONIN GENE RELATED PEPTIDE; CALCITONIN GENE RELATED PEPTIDE RECEPTOR; CALCITONIN GENE RELATED PEPTIDE RECEPTOR ANTAGONIST; G PROTEIN COUPLED RECEPTOR; INDAZOLE DERIVATIVE; INDOLE DERIVATIVE; OLCEGEPANT; PYRIDINE DERIVATIVE; RECEPTOR ACTIVITY MODIFYING PROTEIN 1; TELCAGEPANT; CALCITONIN GENE RELATED PEPTIDE;

AMINO ACID SEQUENCE; AMINO TERMINAL SEQUENCE; ARTICLE; BLOOD PRESSURE; CARBOXY TERMINAL SEQUENCE; CRYSTAL STRUCTURE; DIZZINESS; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; HEADACHE; HIGH THROUGHPUT SCREENING; HUMAN; HYDROGEN BOND; MIGRAINE; MOLECULAR WEIGHT; MUTAGENESIS; NAUSEA; NERVE STIMULATION; NONHUMAN; PHONOPHOBIA; PHOTOPHOBIA; PHYSICAL CHEMISTRY; PLASMA CLEARANCE; PLASMA HALF LIFE; PLASMA PROTEIN BINDING; SOMNOLENCE; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; TRIGEMINUS GANGLION; XEROSTOMIA; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; CLINICAL TRIAL (TOPIC); DRUG DEVELOPMENT; MIGRAINE DISORDERS; MOLECULAR GENETICS; PHYSIOLOGY;

AMINO ACID SEQUENCE; ANIMALS; CALCITONIN GENE-RELATED PEPTIDE; CLINICAL TRIALS AS TOPIC; DRUG DISCOVERY; HUMANS; MIGRAINE DISORDERS; MOLECULAR SEQUENCE DATA; RECEPTORS, CALCITONIN GENE-RELATED PEPTIDE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84907794133     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500364u     Document Type: Article

References (130)

1. Goadsby, P. J.; Lipton, R. B.; Ferrari, M. D. Migraine-current understanding and treatment N. Engl. J. Med. 2002, 346, 257-270
2. Silberstein, S. D. Emerging target-based paradigms to prevent and treat migraine Clin. Pharmacol. Ther. 2013, 93, 78-85
3. Chan, K. Y.; Vermeersch, S.; de Hoon, J.; Villalón, C. M.; MaassenVanDen Brink, A. Potential mechanisms of prospective antimigraine drugs: a focus on vascular (side) effects Pharmacol. Ther. 2011, 129, 332-351
4. Ho, T. W.; Edvinsson, L.; Goadsby, P. J. CGRP and its receptors provide new insights into migraine pathophysiology Nat. Rev. Neurol. 2010, 6, 573-582
5. Eadie, M. J. The pathogenesis of migraine-17th to early 20th century understandings J. Clin. Neurosci. 2005, 12, 383-388
6. Wolff, H. G. Headache and Other Head Pain; Oxford University Press: New York, 1948.
7. Moskowitz, M. A. Neurogenic inflammation in the pathophysiology and treatment of migraine Neurology 1993, 43 (Suppl. 3) S16-S20
8. Silberstein, S. D. Migraine Lancet 2004, 363, 381-391
9. Tfelt-Hansen, P.; De Vries, P.; Saxena, P. R. Triptans in migraine Drugs 2000, 60, 1259-1287
10. Hargreaves, R. New migraine and pain research Headache 2007, 47 (Suppl. 1) S26-S43
11. Amara, S. G.; Jonas, V.; Rosenfeld, M. G.; Ong, E. S.; Evans, R. M. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products Nature 1982, 298, 240-244
12. Edvinsson, L.; Ho, T. W. CGRP receptor antagonism and migraine Neurotherapeutics 2010, 7, 164-175
13. Brain, S. D.; Williams, T. J.; Tippins, J. R.; Morris, H. R.; MacIntyre, I. Calcitonin gene-related peptide is a potent vasodilator Nature 1985, 313, 54-56
14. Edvinsson, L. Functional role of perivascular peptides in the control of cerebral circulation Trends Neurosci. 1985, 8, 126-131
15. Goadsby, P. J.; Edvinsson, L.; Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache Ann. Neurol. 1990, 28, 183-187
16. Goadsby, P. J.; Edvinsson, L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats Ann. Neurol. 1993, 33, 48-56
17. Lassen, L. H.; Haderslev, P. A.; Jacobsen, V. B.; Iversen, H. K. CGRP may play a causative role in migraine Cephalalgia 2002, 22, 54-61
18. Poyner, D. R.; Sexton, P. M.; Marshall, I.; Smith, D. M.; Quirion, R.; Born, W.; Muff, R.; Fischer, J. A.; Foord, S. M. International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors Pharmacol. Rev. 2002, 54, 233-246
19. Woolley, M. J.; Conner, A. C. Comparing the molecular pharmacology of CGRP and adrenomedullin Curr. Protein Pept. Sci. 2013, 14, 358-374
20. Edvinsson, L. Novel migraine therapy with calcitonin gene-related peptide receptor antagonists Expert Opin. Ther. Targets 2007, 11, 1179-1188
21. McLatchie, L. M.; Fraser, N. J.; Main, M. J.; Wise, A.; Brown, J.; Thompson, N.; Solari, R.; Lee, M. G.; Foord, S. M. RAMPs regulate the transport and ligand specificity of the calcitonin receptor-like receptor Nature 1998, 393, 333-339
22. Moore, E. L.; Salvatore, C. A. Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine Br. J. Pharmacol. 2012, 166, 66-78
23. Barwell, J.; Gingell, J. J.; Watkins, H. A.; Archbold, J. K.; Poyner, D. R.; Hay, D. L. Calcitonin and calcitonin-like receptors: common themes with family B GPCRs? Br. J. Pharmacol. 2012, 166, 51-65
24. Hilairet, S.; Foord, S. M.; Marshall, F. H.; Bouvier, M. Protein-protein interaction and not glycosylation determines the binding specificity of heterodimers between the calcitonin receptor-like receptor and the receptor activity-modifying proteins J. Biol. Chem. 2001, 276, 29575-29581
25. Koller, D.; Born, W.; Leuthauser, K.; Fluhmann, B.; McKinney, R. A.; Fischer, J. A.; Muff, R. The extreme N-terminus of the calcitonin-like receptor contributes to the selective interaction with adrenomedullin or calcitonin gene-related peptide FEBS Lett. 2002, 531, 464-468
26. Kuwasako, K.; Kitamura, K.; Nagoshi, Y.; Cao, Y.-N.; Eto, T. Identification of the human receptor activity-modifying protein 1 domains responsible for agonist binding specificity J. Biol. Chem. 2003, 278, 22623-22630
27. Mallee, J. J.; Salvatore, C. A.; LeBourdelles, B.; Oliver, K. R.; Longmore, J.; Koblan, K. S.; Kane, S. A. Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists J. Biol. Chem. 2002, 277, 14294-14298
28. Salvatore, C. A.; Mallee, J. J.; Bell, I. M.; Zartman, C. B.; Williams, T. M.; Koblan, K. S.; Kane, S. A. Identification and pharmacological characterization of domains involved in binding of CGRP receptor antagonists to the calcitonin-like receptor Biochemistry 2006, 45, 1881-1887
29. Miller, P. S.; Barwell, J.; Poyner, D. R.; Wigglesworth, M. J.; Garland, S. L.; Donnelly, D. Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74 Biochem. Biophys. Res. Commun. 2010, 391, 437-442
30. Moore, E. L.; Gingell, J. J.; Kane, S. A.; Hay, D. L.; Salvatore, C. A. Mapping the CGRP receptor ligand binding domain: tryptophan-84 of RAMP1 is critical for agonist and antagonist binding Biochem. Biophys. Res. Commun. 2010, 394, 141-145
31. Barwell, J.; Conner, A.; Poyner, D. R. Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor function Biochim. Biophys. Acta 2011, 1813, 1906-1916
32. Hoare, S. R. J. Mechanisms of peptide and nonpeptide ligand binding to class B G-protein-coupled receptors Drug Discovery Today 2005, 10, 417-427
33. Zartman, C. B.; Bell, I. M.; Gallicchio, S. N.; Graham, S. L.; Kane, S. A.; Mallee, J. J.; Rutledge, R. Z.; Salvatore, C. A.; Vacca, J. P.; Williams, T. M. Identification of a novel RAMP-independent CGRP receptor antagonist Bioorg. Med. Chem. Lett. 2011, 21, 6705-6708
34. Rosenbaum, D. M.; Rasmussen, S. G. F.; Kobilka, B. K. The structure and function of G-protein-coupled receptors Nature 2009, 459, 356-363
35. Koth, C. M.; Abdul-Manan, N.; Lepre, C. A.; Connolly, P. J.; Yoo, S.; Mohanty, A. K.; Lippke, J. A.; Zwahlen, J.; Coll, J. T.; Doran, J. D.; Garcia-Guzman, M.; Moore, J. M. Refolding and characterization of a soluble ectodomain complex of the calcitonin gene-related peptide receptor Biochemistry 2010, 49, 1862-1872
36. ter Haar, E.; Koth, C. M.; Abdul-Manan, N.; Swenson, L.; Coll, J. T.; Lippke, J. A.; Lepre, C. A.; Garcia-Guzman, M.; Moore, J. M. Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism Structure 2010, 18, 1083-1093
37. Pioszak, A.; Xu, H. Molecular recognition of parathyroid hormone by its G protein-coupled receptor Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 5034-5039
38. Parthier, C.; Kleinschmidt, M.; Neumann, P.; Rudolph, R.; Manhart, S.; Schlenzig, D.; Fanghänel, J.; Rahfeld, J.; Demuth, H.; Stubbs, M. Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 13942-13947
39. Kusano, S.; Kukimoto-Niino, M.; Akasaka, R.; Toyama, M.; Terada, T.; Shirouzu, M.; Shindo, T.; Yokoyama, S. Crystal structure of the human receptor activity-modifying protein 1 extracellular domain Protein Sci. 2008, 17, 1907-1914
40. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. A.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists J. Med. Chem. 1988, 31, 2235-2246
41. 2-[3,5-dibromo- N -[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]- d -tyrosyl]- l -lysyl]-4-(4-pyridinyl)piperazine: the first CGRP antagonist for clinical trials in acute migraine J. Med. Chem. 2005, 48, 5921-5931
42. Paone, D. V.; Shaw, A. W.; Nguyen, D. N.; Burgey, C. S.; Deng, J. Z.; Kane, S. A.; Koblan, K. S.; Salvatore, C. A.; Mosser, S. D.; Johnston, V. K.; Wong, B. K.; Miller-Stein, C. M.; Hershey, J. C.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: discovery of N -[(3 R,6 S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-1-yl)piperidine-1-carboxamide (MK-0974) J. Med. Chem. 2007, 50, 5564-5567
43. Hay, D. L.; Christopoulos, G.; Christopoulos, A.; Sexton, P. M. Determinants of BIBN4096BS affinity for calcitonin gene-related peptide and amylin receptors-the role of receptor activity modifying protein 1 Mol. Pharmacol. 2006, 70, 1984-1991
44. Doods, H.; Hallermayer, G.; Wu, D.; Entzeroth, M.; Rudolf, K.; Engel, W.; Eberlein, W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist Br. J. Pharmacol. 2000, 129, 420-423
45. Hershey, J. C.; Corcoran, H. A.; Baskin, E. P.; Salvatore, C. A.; Mosser, S.; Williams, T. M.; Koblan, K. S.; Hargreaves, R.; Kane, S. A. Investigation of the species selectivity of a nonpeptide CGRP receptor antagonist using a novel pharmacodynamic assay Regul. Pept. 2005, 127, 71-77
46. Salvatore, C.; Breese, R.; Chen, R.; Lyle, E.; Corcoran, H.; Hershey, J.; Vogt, T.; Williams, T.; Koblan, K.; Kane, S. Humanization of mouse RAMP1 via targeted recombination confers human-like pharmacology of CGRP receptor antagonists. Presented at the 35th Annual Meeting of the Society for Neuroscience, Washington, DC, U.S., November 12-16, 2005.
47. Olesen, J.; Diener, H.-C.; Husstedt, I. W.; Goadsby, P. J.; Hall, D.; Meier, U.; Pollentier, S.; Lesko, L. M. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine N. Engl. J. Med. 2004, 350, 1104-1110
48. Rudolf, K.; Mueller, S.; Stenkamp, D.; Lustenberger, P.; Dreyer, A.; Schaenzle, G.; Bauer, E.; Santagostino, M.; Paleari, F.; Nolte, T.; Beilmann, M.; Schindler, M.; Arndt, K.; Doods, H. Abstracts of Papers, 241st National Meeting and Exposition of the American Chemical Society, Anaheim, CA, U.S., March 27-31, 2011; American Chemical Society: Washington, DC, 2011; MEDI 11.
49. Williams, T. M.; Stump, C. A.; Nguyen, D. N.; Quigley, A. G.; Bell, I. M.; Gallicchio, S. N.; Zartman, C. B.; Wan, B.-L.; Della Penna, K.; Kunapuli, P.; Kane, S. A.; Koblan, K. S.; Mosser, S. D.; Rutledge, R. Z.; Salvatore, C.; Fay, J. F.; Vacca, J. P.; Graham, S. L. Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead Bioorg. Med. Chem. Lett. 2006, 16, 2595-2598
50. Burgey, C. S.; Stump, C. A.; Nguyen, D. N.; Deng, J. Z.; Quigley, A. G.; Norton, B. R.; Bell, I. M.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan, K. S.; Vacca, J. P.; Graham, S. L.; Williams, T. M. Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: optimization of the 4-substituted piperidine Bioorg. Med. Chem. Lett. 2006, 16, 5052-5056
51. Shaw, A. W.; Paone, D. V.; Nguyen, D. N.; Stump, C. A.; Burgey, C. S.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan, K. S.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Caprolactams as potent CGRP receptor antagonists for the treatment of migraine Bioorg. Med. Chem. Lett. 2007, 17, 4795-4798
52. Salvatore, C. A.; Hershey, J. C.; Corcoran, H. A.; Fay, J. F.; Johnston, V. K.; Moore, E. L.; Mosser, S. D.; Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Graham, S. L.; Vacca, J. P.; Williams, T. M.; Koblan, K. S.; Kane, S. A. Pharmacological characterization of MK-0974 [ N -[(3 R,6 S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine J. Pharmacol. Exp. Ther. 2008, 324, 416-421
53. Moore, E. L.; Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Tang, Y. S.; Kane, S. A.; Salvatore, C. A. Examining the binding properties of MK-0974: a CGRP receptor antagonist for the acute treatment of migraine Eur. J. Pharmacol. 2009, 602, 250-254
54. Van der Schueren, B. J.; de Hoon, J. N.; Vanmolkot, F. H.; Van Hecken, A.; Depre, M.; Kane, S. A.; De Lepeleire, I.; Sinclair, S. R. Reproducibility of the capsaicin-induced dermal blood flow response as assessed by laser Doppler perfusion imaging Br. J. Clin. Pharmacol. 2007, 64, 580-590
55. Paone, D. V.; Shaw, A.; Nguyen, D.; Burgey, C.; Deng, J.; Stump, C.; Quigley, A.; DeSolms, J.; Kane, S.; Koblan, K.; Bednar, R.; Mallee, J.; Mosser, S.; Salvatore, C.; McMasters, D.; Hershey, J.; Corcoran, H.; Lyle, B.; Wong, B.; Roller, S.; Miller-Stein, C.; Rowe, J.; Yu, S.; Graham, S.; Vacca, J.; Williams, T. Abstracts of Papers, 233rd National Meeting and Exposition of the American Chemical Society, Chicago, IL, U.S., March 25-29, 2007; American Chemical Society: Washington, DC, 2007; MEDI 20.
56. Roller, S.; Cui, D.; Laspina, C.; Miller-Stein, C.; Rowe, J.; Wong, B.; Prueksaritanont, T. Preclinical pharmacokinetics of MK-0974, an orally active calcitonin gene-related peptide (CGRP)-receptor antagonist, mechanism of dose dependency and species differences Xenobiotica 2009, 39, 33-45
57. Paone, D. V.; Nguyen, D. N.; Shaw, A. W.; Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Mosser, S. D.; Salvatore, C. A.; Yu, S.; Roller, S.; Kane, S. A.; Selnick, H. G.; Vacca, J. P.; Williams, T. M. Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918 Bioorg. Med. Chem. Lett. 2011, 21, 2683-2686
58. Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Mosser, S. D.; Salvatore, C. A.; Yu, S.; Roller, S.; Kane, S. A.; Vacca, J. P.; Williams, T. M. Optimization of azepanone calcitonin gene-related peptide (CGRP) receptor antagonists: development of novel spiropiperidines Bioorg. Med. Chem. Lett. 2009, 19, 6368-6372
59. Bell, I. M.; Bednar, R. A.; Fay, J. F.; Gallicchio, S. N.; Hochman, J. H.; McMasters, D. R.; Miller-Stein, C.; Moore, E. L.; Mosser, S. D.; Pudvah, N. T.; Quigley, A. G.; Salvatore, C. A.; Stump, C. A.; Theberge, C. R.; Wong, B. K.; Zartman, C. B.; Zhang, X.-F.; Kane, S. A.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists Bioorg. Med. Chem. Lett. 2006, 16, 6165-6169
60. Wood, M. R.; Schirripa, K. M.; Kim, J. J.; Quigley, A. G.; Stump, C. A.; Bell, I. M.; Bednar, R. A.; Fay, J. F.; Bruno, J. G.; Moore, E. L.; Mosser, S. D.; Roller, S.; Salvatore, C. A.; Vacca, J. P.; Selnick, H. G. Novel CGRP receptor antagonists through a design strategy of target simplification with additional molecular flexibility Bioorg. Med. Chem. Lett. 2009, 19, 5787-5790
61. Stump, C. A.; Bell, I. M.; Bednar, R. A.; Bruno, J. G.; Fay, J. F.; Gallicchio, S. N.; Johnston, V. K.; Moore, E. L.; Mosser, S. D.; Quigley, A. G.; Salvatore, C. A.; Theberge, C. R.; Zartman, C. B.; Zhang, X.-F.; Kane, S. A.; Graham, S. L.; Vacca, J. P.; Williams, T. M. The discovery of highly potent CGRP receptor antagonists Bioorg. Med. Chem. Lett. 2009, 19, 214-217
62. Bell, I. M.; Gallicchio, S. N.; Wood, M. R.; Quigley, A. G.; Stump, C. A.; Zartman, C. B.; Fay, J. F.; Li, C.-C.; Lynch, J. J.; Moore, E. L.; Mosser, S. D.; Prueksaritanont, T.; Regan, C. R.; Roller, S.; Salvatore, C. A.; Kane, S. A.; Vacca, J. P.; Selnick, H. G. Discovery of MK-3207: a highly potent, orally bioavailable CGRP receptor antagonist ACS Med. Chem. Lett. 2010, 1, 24-29
63. Salvatore, C. A.; Moore, E. L.; Calamari, A.; Cook, J. J.; Michener, M. S.; OMalley, S.; Miller, P. J.; Sur, C.; Williams, D. L.; Zeng, Z.; Danziger, A.; Lynch, J. J.; Regan, C. R.; Fay, J. F.; Tang, Y. S.; Li, C.-C.; Pudvah, N. T.; White, R. B.; Bell, I. M.; Gallicchio, S. N.; Graham, S. L.; Selnick, H. G.; Vacca, J. P.; Kane, S. A. Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist J. Pharmacol. Exp. Ther. 2010, 333, 152-160
64. Bell, I. M. Abstracts of Papers, 237th National Meeting and Exposition of the American Chemical Society, Salt Lake City, UT, U.S., March 22-26, 2009; American Chemical Society: Washington, DC, 2009; MEDI 28.
65. Bell, I. M.; Stump, C. A.; Gallicchio, S. N.; Staas, D. D.; Zartman, C. B.; Moore, E. L.; Sain, N.; Urban, M.; Bruno, J. G.; Calamari, A.; Kemmerer, A. L.; Mosser, S. D.; Fandozzi, C.; White, R. B.; Zrada, M. M.; Selnick, H. G.; Graham, S. L.; Vacca, J. P.; Kane, S. A.; Salvatore, C. A. MK-8825: A potent and selective CGRP receptor antagonist with good oral activity in rats Bioorg. Med. Chem. Lett. 2012, 22, 3941-3945
66. Greco, R.; Mangione, A. S.; Siani, F.; Blandini, F.; Vairetti, M.; Nappi, G.; Sandrini, G.; Buzzi, M. G.; Tassorelli, C. Effects of CGRP receptor antagonism in nitroglycerin-induced hyperalgesia. Cephalalgia [Online early access]. DOI: 10.1177/0333102413517776. Published online: December 23, 2013.
67. Feistel, S.; Albrecht, S.; Messlinger, K. The calcitonin gene-related peptide receptor antagonist MK-8825 decreases spinal trigeminal activity during nitroglycerin infusion J. Headache Pain 2013, 14, 93
68. 11C]MK-4232: the first positron emission tomography tracer for the calcitonin gene-related peptide receptor ACS Med. Chem. Lett. 2013, 4, 863-868
69. 11C]MK-4232 J. Pharmacol. Exp. Ther. 2013, 347, 478-486
70. Chaturvedula, P. V.; Pin, S.; Thalody, G.; Conway, C. M.; Macor, J. E.; Dubowchik, G. M. Design and synthesis of potent antagonists containing rigid spirocyclic privileged structures for the CGRP receptor Bioorg. Med. Chem. Lett. 2012, 22, 4719-4722
71. Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D. A.; Davis, C. D.; Denton, R.; Han, X.; Macci, R.; Mathias, N. R.; Moench, P.; Pin, S. S.; Ren, S. X.; Schartman, R.; Signor, L. J.; Thalody, G.; Widmann, K. A.; Xu, C.; Macor, J. E.; Dubowchik, G. M. Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4 H)-yl)- N -(3-(7-methyl-1 H -indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure J. Med. Chem. 2008, 51, 4858-4861
72. Han, X.; Civiello, R. L.; Conway, C. M.; Cook, D. A.; Davis, C. D.; Macci, R.; Pin, S. S.; Ren, S. X.; Schartman, R.; Signor, L. J.; Thalody, G.; Widmann, K. A.; Xu, C.; Chaturvedula, P. V.; Macor, J. E.; Dubowchik, G. M. The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 1 Bioorg. Med. Chem. Lett. 2012, 22, 4723-4727
73. Han, X.; Civiello, R. L.; Conway, C. M.; Cook, D. A.; Davis, C. D.; Degnan, A. P.; Jiang, X.-J.; Macci, R.; Mathias, N. R.; Moench, P.; Pin, S. S.; Schartman, R.; Signor, L. J.; Thalody, G.; Tora, G.; Whiterock, V.; Xu, C.; Macor, J. E.; Dubowchik, G. M. The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2 Bioorg. Med. Chem. Lett. 2013, 23, 1870-1873
74. Chaturvedula, P. V.; Mercer, S. E.; Pin, S. S.; Thalody, G.; Xu, C.; Conway, C. M.; Keavy, D.; Signor, L.; Cantor, G. H.; Mathias, N.; Moench, P.; Denton, R.; Macci, R.; Schartman, R.; Whiterock, V.; Davis, C.; Macor, J. E.; Dubowchik, G. M. Discovery of (R)- N -(3-(7-methyl-1 H -indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): a potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery Bioorg. Med. Chem. Lett. 2013, 23, 3157-3161
75. Luo, G.; Chen, L.; Civiello, R.; Pin, S. S.; Xu, C.; Kostich, W.; Kelley, M.; Conway, C. M.; Macor, J. E.; Dubowchik, G. M. Calcitonin gene-related peptide (CGRP) receptor antagonists: pyridine as a replacement for a core amide group Bioorg. Med. Chem. Lett. 2012, 22, 2917-2921
76. Luo, G.; Chen, L.; Conway, C. M.; Keavy, D.; Denton, R.; Kostich, W.; Mercer, S.; Schartman, R.; Signor, L.; Lentz, K.; Browning, M.; Macor, J. E.; Dubowchik, G. M. Discovery of BMS-846372, a potent and orally active human CGRP receptor antagonist for the treatment of migraine ACS Med. Chem. Lett. 2012, 3, 337-341
77. Luo, G.; Chen, L.; Conway, C. M.; Denton, R.; Keavy, D.; Signor, L.; Kostich, W.; Lentz, K. A.; Santone, K. S.; Schartman, R.; Browning, M.; Tong, G.; Houston, J. G.; Dubowchik, G. M.; Macor, J. E. Discovery of (5 S,6 S,9 R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5 H -cyclohepta[ b ]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): an oral calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine J. Med. Chem. 2012, 55, 10644-10651
78. Edvinsson, L.; Warfvinge, K. CGRP receptor antagonism and migraine therapy Curr. Protein Pept. Sci. 2013, 14, 386-392
79. Iovino, M.; Feifel, U.; Yong, C.-L.; Wolters, J.-M.; Wallenstein, G. Safety, tolerability and pharmacokinetics of BIBN 4096 BS, the first selective small molecule calcitonin gene-related peptide receptor antagonist, following single intravenous administration in healthy volunteers Cephalalgia 2004, 24, 645-656
80. Han, T. H.; Blanchard, R. L.; Palcza, J.; McCrea, J. B.; Laethem, T.; Willson, K.; Xu, Y.; Ermlich, S.; Boyle, J.; Lines, C.; Gutierrez, M.; Van Bortel, L.; Xiao, A. J.; Sinclair, S.; Hickey, L.; Panebianco, D.; Murphy, M. G. Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults J. Clin. Pharmacol. 2010, 50, 1367-1376
81. Han, T. H.; Blanchard, R. L.; Palcza, J.; Martucci, A.; Miller-Stein, C. M.; Gutierrez, M.; Panebianco, D.; Rippley, R. K.; Lines, C.; Murphy, M. G. The dose proportionality of telcagepant after administration of single oral and intravenous doses in healthy adult subjects Arch. Drug Inf. 2010, 3, 55-62
82. Sinclair, S. R.; Kane, S. A.; Van der Schueren, B. J.; Xiao, A.; Willson, K. J.; Boyle, J.; de Lepeleire, I.; Xu, Y.; Hickey, L.; Denney, W. S.; Li, C.-C.; Palcza, J.; Vanmolkot, F. H. M.; Depré, M.; Van Hecken, A.; Murphy, M. G.; Ho, T. W.; de Hoon, J. N. Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974) Br. J. Clin. Pharmacol. 2010, 69, 15-22
83. Ho, T. W.; Mannix, L. K.; Fan, X.; Assaid, C.; Furtek, C.; Jones, C. J.; Lines, C. R.; Rapoport, A. M. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in the acute treatment of migraine Neurology 2008, 70, 1304-1312
84. Ho, T. W.; Ferrari, M. D.; Dodick, D. W.; Galet, V.; Kost, J.; Fan, X.; Leibensperger, H.; Froman, S.; Assaid, C.; Lines, C.; Koppen, H.; Winner, P. K. Efficacy and tolerability of MK-0974 (telcagepant), an new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial Lancet 2008, 372, 2115-2123
85. Connor, K. M.; Shapiro, R. E.; Diener, H.-C.; Lucas, S.; Kost, J.; Fan, X.; Fei, K.; Assaid, C.; Lines, C.; Ho, T. W. Randomized, controlled trial of telcagepant for the acute treatment of migraine Neurology 2009, 73, 970-977
86. Ho, A. P.; Dahlöf, C. G. H.; Silberstein, S. D.; Saper, J. R.; Ashina, M.; Kost, J. T.; Froman, S.; Leibensperger, H.; Lines, C. R.; Ho, T. W. Randomized, controlled trial of telcagepant over four migraine attacks Cephalalgia 2010, 30, 1443-1457
87. Connor, K. M.; Aurora, S. K.; Loeys, T.; Ashina, M.; Jones, C.; Giezek, H.; Massaad, R.; Williams-Diaz, A.; Lines, C.; Ho, T. W. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial Headache 2011, 51, 73-84
88. Brandes, J. L.; Kudrow, D.; Stark, S. R.; OCarroll, C. P.; Adelman, J. U.; ODonnell, F. J.; Alexander, W. J.; Spruill, S. E.; Barrett, P. S.; Lener, S. E. Sumatriptan-naproxen for acute treatment of migraine JAMA, J. Am. Med. Assoc. 2007, 297, 1443-1454
89. Hewitt, D. J.; Martin, V.; Lipton, R. B.; Brandes, J.; Ceesay, P.; Gottwald, R.; Schaefer, E.; Lines, C.; Ho, T. W. Randomized controlled study of telcagepant plus ibuprofen or acetaminophen in migraine Headache 2011, 51, 533-543
90. Edvinsson, L.; Alm, R.; Shaw, D.; Rutledge, R. Z.; Koblan, K. S.; Longmore, J.; Kane, S. A. Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells Eur. J. Pharmacol. 2002, 434, 49-53
91. Chan, K. Y.; Edvinsson, L.; Eftekhari, P. O.; Kimblad, S. A.; Kane, S. A.; Lynch, J.; Hargreaves, R. J.; de Vries, R.; Garrelds, I. M.; van den Bogaerdt, A. J.; Danser, A. H. J.; MaassenVanDenBrink, A. Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries J. Pharmacol. Exp. Ther. 2010, 334, 746-752
92. Lynch, J. J.; Regan, C. P.; Edvinsson, L.; Hargreaves, R. J.; Kane, S. A. Comparison of the vasoconstrictor effects of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) and zolmitriptan in human isolated coronary arteries J. Cardiovasc. Pharmacol. 2010, 55, 518-521
93. Depré, M.; MacLeod, C.; Palcza, J.; Behm, M. O.; de Lepeleire, I.; Han, T.; Panebianco, D.; Smith, W. B.; Blanchard, R.; Chodakewitz, J. A.; Murphy, M. G.; de Hoon, J. N. Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: results from a randomized study in patients with migraine Cephalalgia 2013, 33, 1292-1301
94. Van der Schueren, B. J.; Blanchard, R.; Murphy, M. G.; Palcza, J.; de Lepeleire, I.; Van Hecken, A.; Depré, M.; de Hoon, J. N. The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men Br. J. Clin. Pharmacol. 2011, 71, 708-717
95. Behm, M. O.; Blanchard, R. L.; Murphy, M. G.; Palcza, J.; Harris, D. E.; Butterfield, K. L.; Smith, W. B.; Preston, R. A.; Chodakewitz, J. A.; Krucoff, M. W. Effect of telcagepant on spontaneous ischemia in cardiovascular patients in a randomized study Headache 2011, 51, 954-960
96. Chaitman, B. R.; Ho, A. P.; Behm, M. O.; Rowe, J. F.; Palcza, J.; Laethem, T.; Heirman, I.; Panebianco, D.; Kobalava, Z.; Martsevich, S. Y.; Free, A. L.; Bittar, N.; Chrysant, S. G.; Ho, T. W.; Chodakewitz, J. A.; Murphy, M. G.; Blanchard, R. L. A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina Clin. Pharmacol. Ther. 2012, 91, 459-466
97. ClinicalTrials.gov. MK0974 for Migraine Prophylaxis in Patients with Episodic Migraine (0974-049). http://www.clinicaltrials.gov/show/NCT00797667 (accessed Feb 13, 2014).
98. Merck News Release. Merck announces second quarter 2011 financial results. July 29, 2011.
99. Diener, H.-C.; Barbanti, P.; Dahlöf, C.; Reuter, U.; Habeck, J.; Podhorna, J. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study Cephalalgia 2011, 31, 573-584
100. Hewitt, D. J.; Aurora, S. K.; Dodick, D. W.; Goadsby, P. J.; Ge, Y. J.; Bachman, R.; Taraborelli, D.; Fan, X.; Assaid, C.; Lines, C.; Ho, T. W. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine Cephalalgia 2011, 31, 712-722
101. Marcus, R.; Goadsby, P. J.; Dodick, D.; Stock, D.; Manos, G.; Fischer, T. Z. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial Cephalalgia 2014, 34, 114-125
102. Luo, G.; Chen, L.; Dubowchik, G. M.; Keavy, D.; Signor, L.; Kostich, W.; Conway, C. M.; Lentz, K.; Denton, R.; Schartman, R.; Fan, Y.; Leahy, D.; Tong, G.; Houston, J. G.; Macor, J. E. Abstracts of Papers, 243rd National Meeting and Exposition of the American Chemical Society, San Diego, CA, U.S., March 25-29, 2012; American Chemical Society: Washington, DC, 2012; MEDI 20.
103. Armstrong, D. Bristol-Myers may sell experimental migraine drug. Bloomberg 2013, Jan 7; http://www.bloomberg.com/news/2013-01-07/bristol-meyers-may-sell-experimental-migraine-drug.html (accessed Feb 13, 2014).
104. Tepper, S. J.; Stillman, M. J. Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine Headache 2008, 48, 1259-1268
105. Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes ACS Chem. Neurosci. 2010, 1, 420-434
106. Edvinsson, L.; Nilsson, E.; Jansen-Olesen, I. Inhibitory effect of BIBN4096BS, CGRP8-37, a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non perfused rat middle cerebral artery Br. J. Pharmacol. 2007, 150, 633-640
107. Fischer, M. J. M.; Koulchitsky, S.; Messlinger, K. The nonpeptide calcitonin gene-related peptide receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal trigeminal nucleus J. Neurosci. 2005, 25, 5877-5883
108. Covasala, O.; Stirn, S. L.; Albrecht, S.; De Col, R.; Messlinger, K. Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity J. Neurophysiol. 2012, 108, 431-440
109. Hirsch, S.; Corradini, L.; Just, S.; Arndt, K.; Doods, H. The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats Pain 2013, 154, 700-707
110. Bullock, C. M.; Kelly, S. Calcitonin gene-related peptide receptor antagonists: beyond migraine pain-a possible analgesic strategy for osteoarthritis? Curr. Pain Headache Rep. 2013, 17, 375
111. Oliver, K. R.; Wainwright, A.; Edvinsson, L.; Pickard, J. D.; Hill, R. G. Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature J. Cereb. Blood Flow Metab. 2002, 22, 620-629
112. Eftekhari, S.; Salvatore, C. A.; Calamari, A.; Kane, S. A.; Tajti, J.; Edvinsson, L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion Neuroscience 2010, 169, 683-696
113. Eftekhari, S.; Salvatore, C. A.; Chen, T.-B.; Zeng, Z.; Edvinsson, L. Trigeminal ganglion-a site of action for CGRP receptor antagonists Cephalalgia 2013, 33, 954 (Late-Breaking Abstracts of the 2013 International Headache Congress, Boston, MA, June 27-30, 2013; LBO1)
114. Petersen, K. A.; Birk, S.; Lassen, L. H.; Kruuse, C.; Jonassen, O.; Lesko, L.; Olesen, J. The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers Cephalalgia 2004, 25, 139-147
115. Petersen, K. A.; Lassen, L. H.; Birk, S.; Lesko, L.; Olesen, J. BIBN4096BS antagonizes human -calcitonin gene related peptide-induced headache and extracerebral artery dilatation Clin. Pharmacol. Ther. 2005, 77, 202-213
116. Asghar, M. S.; Hansen, A. E.; Amin, F. M.; van der Geest, R. J.; van der Koning, P.; Larsson, H. B. W.; Olesen, J.; Ashina, M. Evidence for a vascular factor in migraine Ann. Neurol. 2011, 69, 635-645
117. Amin, F. M.; Asghar, M. S.; Hougaard, A.; Hansen, A. E.; Larsen, V. A.; de Koning, P. J. H.; Larsson, H. B. W.; Olesen, J.; Ashina, M. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study Lancet Neurol. 2013, 12, 454-461
118. Tfelt-Hansen, P.; Olesen, J. Possible site of action of CGRP antagonists in migraine Cephalalgia 2011, 31, 748-750
119. Grimwood, S.; Hartig, P. R. Target site occupancy: emerging generalizations from clinical and preclinical studies Pharmacol. Ther. 2009, 122, 281-301
120. Kim, J. J.; Wood, M. R.; Stachel, S. J.; de Leon, P.; Nomland, A.; Stump, C. A.; McWherter, M. A.; Schirripa, K. M.; Moore, E. L.; Salvatore, C. A.; Selnick, H. G. (E)-Alkenes as replacements of amide bonds: development of novel and potent acyclic CGRP receptor antagonists Bioorg. Med. Chem. Lett. 2014, 24, 258-261
121. Joshi, P.; Anderson, C.; Binch, H.; Hadida, S.; Yoo, S.; Bergeron, D.; Decker, C.; terHaar, E.; Moore, J.; Garcia-Guzman, M.; Termin, A. Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists Bioorg. Med. Chem. Lett. 2014, 24, 845-849
122. Ho, T. W.; Olesen, J.; Dodick, D. W.; Kost, J.; Lines, C.; Ferrari, M. D. Antimigraine efficacy of telcagepant based on patients historical triptan response Headache 2011, 51, 64-72
123. Goadsby, P. J.; Sprenger, T. Current practice and future directions in the prevention and acute management of migraine Lancet Neurol. 2010, 9, 285-298
124. ClinicalTrials.gov. A study of LY2951742 in patients with migraine. http://www.clinicaltrials.gov/show/NCT01625988 (accessed Feb 15, 2014).
125. ClinicalTrials.gov. Safety, efficacy and pharmacokinetics of ALD403. http://www.clinicaltrials.gov/show/NCT01772524 (accessed Feb 15, 2014).
126. ClinicalTrials.gov. A phase 2 study to evaluate the efficacy and safety of AMG 334 in migraine prevention. http://www.clinicaltrials.gov/show/NCT01952574 (accessed Feb 15, 2014).
127. ClinicalTrials.gov. Assessment of LBR-101 in chronic migraine. http://www.clinicaltrials.gov/show/NCT02021773 (accessed Feb 15, 2014).
128. Bigal, M. E.; Walter, S.; Rapoport, A. M. Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development Headache 2013, 53, 1230-1244
129. Dodick, D.; Goadsby, P.; Spierings, E.; Scherer, J.; Sweeney, S.; Grayzel, D. CGRP monoclonal antibody LY2951742 for the prevention of migraine: a phase 2, randomized, double-blind, placebo-controlled study. Presented at the 66th Annual Meeting of the American Academy of Neurology, Philadelphia, PA, U.S., April 26-May 3, 2014.
130. Goadsby, P.; Dodick, D.; Silberstein, S.; Lipton, R.; Olesen, J.; Ashina, M.; Wilks, K.; Kudrow, D.; Kroll, R.; Kohrman, B.; Bargar, R.; Woodinville, J.; Smith, J. Randomized, double-blind, placebo-controlled trial of ALD403, and anti-CGRP peptide antibody in the prevention of frequent episodic migraine. Presented at the 66th Annual Meeting of the American Academy of Neurology, Philadelphia, PA, U.S., April 26-May 3, 2014.