8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: Selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists

Journal of Medicinal Chemistry

Volumn 52, Issue 9, 2009, Pages 3073-3083

  Gilligan, Paul J ^a   He, Liqi ^a   Clarke, Todd ^a   Tivitmahaisoon, Parcharee ^a   Lelas, Snjezana ^a   Li, Yu Wen ^a   Heman, Karen ^a   Fitzgerald, Lawrence ^b   Miller, Keith ^a   Zhang, Ge ^a   Marshall, Anne ^a   Krause, Carol ^a   McElroy, John ^d   Ward, Kathyrn ^a   Shen, Helen ^a   Wong, Harvey ^a   Grossman, Scott ^a   Nemeth, Gregory ^a   Zaczek, Robert ^a   Arneric, Stephen P ^c   Hartig, Paul ^a   Robertson, David W ^d   Trainor, George ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

^b PFIZER INC   (United States)

^c ELI LILLY AND COMPANY   (United States)

^d Jenrin Discovery   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [BIS(2 METHOXYETHYL)AMINO] 2,7 DIMETHYL 8 (2 METHYL 4 METHOXYPHENYL)[1,5 A]PYRAZOLO 1,3,5 TRIAZINE; 8 (4 METHOXYPHENYL)PYRAZOLO[1,5 A] 1,3,5 TRIAZINE DERIVATIVE; CORTICOTROPIN RELEASING FACTOR ANTAGONIST; CORTICOTROPIN RELEASING FACTOR RECEPTOR 1; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DOG; DRUG CLEARANCE; DRUG HALF LIFE; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; MALE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION; TRANQUILIZING ACTIVITY;

ANIMALS; ANTI-ANXIETY AGENTS; ANXIETY; CLINICAL TRIALS AS TOPIC; DOGS; FEMALE; INHIBITORY CONCENTRATION 50; MALE; RATS; RECEPTORS, BIOGENIC AMINE; RECEPTORS, CORTICOTROPIN-RELEASING HORMONE; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY; TRIAZINES;

EID: 65649118273     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9000242     Document Type: Article

References (56)

1. Dzierba, C. D.; Hartz, R. A.; Bronson, J. J. Recent advances in corticotropin-releasing factor antagonists. Annu. Rep. Med. Chem. 2008, 43, 3-23.
2. Tellew, J. E.; Luo, Z. Small molecule antagonists of the corticotropin-releasing factor (CRF) receptor: recent medicinal chemistry developments. Curr. Top. Med. Chem. 2008, 8, 506-520.
3. Gilligan, P. J.; Robertson, D. W.; Zaczek, R. Corticotropin releasing factor (CRF) receptor modulators: progress and opportunities for new therapeutic agents. J. Med. Chem. 2000, 43, 1641-1660. (Pubitemid 30304997)
4. McCarthy, J. R.; Heinrichs, S. C.; Grigoriadis, D. E. Recent advances with the CRF1 receptor: Design of small molecule inhibitors, receptor subtypes and clinical indications. Curr. Pharm. Des. 1999, 5, 289-315. (Pubitemid 29238994)
5. Gilligan, P. J. Corticotropin-releasing factor receptor antagonists. Expert Opin. Ther. Pat. 2006, 16, 913-924.
6. Dunn, A. J.; Berridge, C. W. Physiological and behavioral responses to corticotropin-releasing factor administration: Is CRF a mediator of anxiety or stress responses? Brain Res. Rev. 1990, 15, 71-100.
7. Stenzel-Poore, M. P.; Heinrichs, S. C.; Rivest, R.; Koob, G. F.; Vale, W. W. Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J. Neurosci. 1994, 14, 2579-2584. (Pubitemid 24140886)
8. Majzoub, J. A.; Muglia, L. J.; Martinez, C.; Jacobson, L. Molecular and transgenic studies of the corticotropin-releasing hormone gene. Ann. N.Y. Acad. Sci. 1995, 771, 293-300. (Pubitemid 26077415)
9. Gulyas, J.; Rivier, C.; Perrin, M.; Koerber, S. C.; Sutton, S.; Corrigan, A.; Lahrichi, S. L.; Craig, A. J.; Vale, W.; Rivier, J. Potent, structurally constrained agonists and competitive antagonists of corticotropin-releasing factor. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575-10579.
10. Perrin, M. H.; Sutton, S. W.; Cervini, L. A.; Rivier, J.; Vale, W. W. Comparison of an agonist, urocortin, and an antagonist, astressin, as radioligands for characterization of corticotropin-releasing factor receptors. J. Pharmacol. Exp. Ther. 1999, 288, 729-734. (Pubitemid 29119688)
11. Vale, W.; Spiess, J.; Rivier, C.; Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981, 213, 1394-1397. (Pubitemid 12243637)
12. Valentino, R. J.; Foote, S. L. Brain Noradrenergic Neurons, Corticotropin Releasing Factor and Stress. In Neural and Endocrine Peptides and Receptors; Moody, T., Ed.; Plenum Press: New York, 1986; pp 101-120.
13. Davies, M. The role of the amygdala in fear and anxiety. Annu. Rev. Neurosci. 1993, 15, 353-375.
14. Lehnert, H.; Schulz, C.; Dieterich, K. Physiological and neurochemical aspects of corticotropin-releasing factor actions in the brain: the role of the locus coeruleus. Neurochem. Res. 1998, 23, 1039-1052. (Pubitemid 28350828)
15. 1 receptor mRNA expression. J. Neurosci. 1995, 15, 6340-6350.
16. Chen, R.; Lewis, K. A.; Perrin, M. H.; Vale, W. W. Expression cloning of a human corticotropin-releasing factor receptor. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8967-8971. (Pubitemid 23306432)
17. Kishimoto, T.; Pearse, R. V.; Lin, C. R.; Rosenfeld, M. G. A sauvagine/corticotropin releasing factor receptor expressed in heart and skeletal muscle. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 1108-1112.
18. Kostich, W. A.; Chen, A.; Sperle, K.; Largent, B. L. Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2γ receptor. Mol. Endocrinol. 1998, 12, 1077-1085. (Pubitemid 30659035)
19. Liaw, C. W.; Lovenberg, T. W.; Barry, G.; Oltersdorf, T.; Grigoriadis, D. E.; De Souza, E. B. Cloning and characterization of the human corticotropin releasing factor-2 receptor complementary deoxyribonucleic acid. Endocrinology 1996, 137, 72-77. (Pubitemid 126424572)
20. 2β receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 1995, 136, 4139-4142.
21. Lovenberg, T. W.; Liaw, C. W.; Grigoriadis, D. E.; Clevenger, W.; Chalmers, D. T.; De Souza, E. B.; Oltersdorf, T. Cloning and characterization of a functionally distinct corticotropin releasing factor receptor subtype from rat brain. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 836-840.
22. Perrin, M.; Donaldson, C.; Chen, R.; Blount, A.; Bergren, T.; Bilezikjian, L.; Sawchenko, P.; Vale, W. W. Identification of a second corticotropin-releasing factor receptor gene and characterization of a c-DNA expressed in heart. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2969-2973.
23. Chalmers, D. T.; Lovenberg, T. W.; Grigoriadis, D. E.; Behan, D. P.; DeSouza, E. B. Corticotropin-releasing factor receptors: from molecular biology to drug design. Trends Pharmacol. Sci. 1996, 17, 166-172. (Pubitemid 26122417)
24. Millan, M. A.; Jacobowitz, D. M.; Hauger, R. L.; Catt, K. J.; Aguilera, G. Distribution of corticotropin-releasing factor receptors in the primate brain. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1921-1925. (Pubitemid 16018675)
25. Grigoriadis, D. E.; Dent, G. W.; Turner, J. G.; Uno, H.; Shelton, S. E.; De Souza, E. B.; Kalin, N. H. Corticotropin-releasing factor (CRF) receptors in infant rhesus monkey brain and pituitary gland: biochemical characterization and autoradiographic localization. Dev. Neurosci. 1995, 17, 357-367. (Pubitemid 26093260)
26. Grigoriadis, D. E.; Lovenberg, T. W.; Chalmers, D. T.; Liaw, C.; De Souza, E. B. Characterization of corticotropin-releasing factor receptor subtypes. Ann. N.Y. Acad. Sci. 1996, 780, 60-80. (Pubitemid 26196970)
27. Miranda, A.; Lahrichi, S. L.; Gulyas, J.; Koerber, S. C.; Craig, A. G.; Corrigan, A.; Rivier, C.; Vale, W.; Rivier, J. Constrained corticotropin- releasing factor antagonists with i-(i+3) Glu-Lys bridges. J. Med. Chem. 1997, 40, 3651-3658. (Pubitemid 27465097)
28. Rivier, J.; Lahrichi, S. L.; Gulyas, J.; Erchegyi, J.; Koerber, S. C.; Craig, A. G.; Corrigan, A.; Rivier, C.; Vale, W. W. Minimal sizeconstrained corticotropin-releasing factor agonists with i-(i+3) Glu-Lys and Lys-Gln bridges. J. Med. Chem. 1998, 41, 2614-2620. (Pubitemid 28321910)
29. 2β-selective antisauvagine-30. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 15264-15269.
30. Schulz, D. W.; Mansbach, R. S.; Sprouse, J.; Braselton, J. P.; Collins, J.; Corman, M.; Dunaiskis, A.; Faraci, S.; Schmidt, A. W.; Seeger, T.; Seymour, P.; Tingley, F. D.; Winston, E. N.; Chen, Y. L.; Heym, J. CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 10477-10482. (Pubitemid 26314648)
31. Mansbach, R. S.; Brooks, E. N.; Chen, Y. L. Antidepressant-like effects of CP154526: a selective CRF1 receptor antagonist. Eur. J. Pharmacol. 1997, 323, 21-26. (Pubitemid 27136433)
32. 1 antagonist. J. Med. Chem. 2000, 430, 449-456.
33. Gilligan, P. J.; Baldauf, C.; Cocuzza, A.; Chidester, D.; Zaczek, R.; Fitzgerald, L. W.; McElroy, J. F.; Smith, M. A.; Shen, H.-S.L.; Saye, J. A.; Christ, D.; Trainor, G.; Robertson, D. W.; Hartig, P. The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl) pyrazolo-[1,5-a]- pyrimidine: a corticotropin-releasing factor antagonist (hCRF1) antagonist. Bioorg. Med. Chem. 2000, 8, 181-189. (Pubitemid 30125667)
34. Gold, P. W.; Loriaux, D. L.; Roy, A.; Kling, M. A.; Calkabrese, J. R.; Kellner, C. H.; Nieman, L. K.; Post, R. M.; Pickar, D.; Gallucci, W.; Augerinos, P.; Paul, S.; Oldfiled, E. H.; Cutler, G. B.; Chrousos, G. P. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. New Engl. J. Med. 1986, 314, 1329-1335.
35. Carroll, B. J.; Curtis, G. C.; Davies, B. M.; Mendels, J.; Sugarman, A. A. Urinary free cortisol secretion in depression. Psychol. Med. 1976, 6, 43-50.
36. Raadsheer, F. C.; Hoogendijk, W. J. G.; Stam, F. C.; Tilders, F. J. H.; Swaab, D. F. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology. 1994, 60, 436-444. (Pubitemid 24284827)
37. Nemeroff, C. B.; Bisette, G.; Akil, H.; Fink, M. Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy: corticotropin-releasing factor, β-endorphin, and somatostatin. Br. J. Psychiatry 1991, 158, 59-63.
38. Banki, C. M.; Karmacsi, L.; Bissette, G.; Nemeroff, C. B. CSF corticotropin releasing hormone and somatostatin in major depression: response to antidepressant treatment and relapse. Eur. Neuropsychopharmacol. 1992, 2, 107-113.
39. DeBellis, M. D.; Gold, P. W.; Geracioti, T. D.; Listwak, S. J.; Kling, M. A. Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am. J. Psychiatry. 1993, 150, 656-657. (Pubitemid 23109940)
40. Kling, M. A.; Geracioti, T. D.; Licinio, D.; Michelson, E. H.; Oldfield, E. H.; Gold, P. W. Effects of electroconvulsive therapy on the CRH-ACTH-cortisol sytem in melancholic depression: preliminary findings. Psychopharmacol. Bull. 1994, 30, 489-494.
41. Zobel, A. W.; Nickel, T.; Kunzel, H. E.; Ackl, N.; Sonntag, A.; Ising, M.; Holsboer, F. Effects of the high affinity corticotropin releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 2000, 34, 171-181. (Pubitemid 30364916)
42. Binneman, B.; Feltner, D.; Kolluri, S.; Shi, Y.; Qiu, R.; Stiger, T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am. J. Psychiatry 2008, 165, 617-620.
43. Chen, Y. L.; Braselton, J.; Forman, J.; Gallaschun, R. J.; Mansbach, R.; Schmidt, A. W.; Seeger, T. F.; Sprouse, J. S.; Tingley, F. D.; Winston, E.; Schulz, D. W. Synthesis and SAR of 2-aryloxy-4-alkoxypyridines as potent orally active corticotropin-releasing factor 1 receptor antagonists. J. Med. Chem. 2008, 51, 1377-1384.
44. He, L.; Gilligan, P. J.; Fitzgerald, L.; Zaczek, R.; Shen, H.; Trainor, G. L.; Hartig, P. R. Pyrazolo-[1,5-a]-s-triazine as Novel hCRF1 Receptor Antagonists: Design, Synthesis and Structure Activity Relationships. Presented at the American Chemical Society National Meeting, Anaheim, CA, March 21-25, 1999; MEDI 107.
45. Zhou, J.; Oh, L. M.; Ma, P. Convergent Synthesis of α-Aryl-β- ketonitriles from Aryl Boronic Acids and Isoxazoles. US 6562965, 2003.
46. DeSouza, E. B. Corticotropin-releasing factor receptors in the rat central nervous system: characterization and regional distribution. J. Neurosci. 1987, 7, 88-100. (Pubitemid 17235470)
47. 1 receptor antagonist DMP696 produces anxiolytic effects and inhibits the stress-induced hypothalamicpituitary- adrenal axis activation without sedation or ataxia in rats. Psychopharmacology 2002, 165, 86-92.
48. 1 receptor antagonists. CNS Drug Rev. 2005, 11, 21-52.
49. Sutton, S. W.; Behan, D. P.; Lahrichi, S. L.; Kaiser, R.; Corrigan, A.; Lowry, P.; Potter, E.; Perrin, M. H.; Rivier, J.; Vale, W. Ligand requirements of the human corticotropin-releasing factor-binding protein. Endocrinology 1995, 136, 1097-1102.
50. Fitzgerald, L. Unpublished results.
51. Gilligan, P. J.; Rabel, S. R.; Meenan, P. A. Salt and Crystalline Form Thereof of a Corticotropin Releasing Factor Receptor Antagonist. U.S. Patent Application US2005113375, 2005.
52. Li, Y.-W.; Hill, G.; Wong, H.; Kelly, N.; Ward, K.; Pierdomenico, M.; Ren, S.; Gilligan, P.; Grossman, S.; Trainor, G.; Taub, R.; McElroy, J.; Zazcek, R. Receptor occupancy of nonpeptide corticotropin- releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy. J. Pharmacol. Exp. Ther. 2003, 305, 86-96. (Pubitemid 36373838)
53. He, L.; Gilligan, P. J.; Arvanitis, A. G.; Chorvat, R. J. Azolo Triazines and Pyrimidines. US 6124289, 2000.
54. Perrin, D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon Press: New York, 1988.
55. Munson, P. J.; Rodbard, D. LIGAND: a versatile computerized approach for characterization of ligand binding systems. Anal. Biochem. 1980, 107, 220-239.
56. Battaglia, G.; Webster, E. L.; De Souza, E. B. Characterization of corticotropin-releasing factor (CRF) receptor-mediated stimulation of adenylate cyclase activity in rat brain. Synapse 1987, 1, 572-581.