Design, synthesis, and biological evaluation of 1,2,3,7-tetrahydro-6H- purin-6-one and 3,7-dihydro-1H-purine-2,6-dione derivatives as corticotropin-releasing factor1 receptor antagonists

Journal of Medicinal Chemistry

Volumn 47, Issue 19, 2004, Pages 4741-4754

  Hartz, Richard A ^a   Nanda, Kausik K ^b   Ingalls, Charles L ^c   Ahuja, Vijay T ^a   Molski, Thaddeus F ^a   Zhang, Ge ^a   Wong, Harvey ^a   Peng, Yong ^a   Kelley, Michelle ^a   Lodge, Nicholas J ^a   Zaczek, Robert ^a   Gilligan, Paul J ^a   Trainor, George L ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

^c PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,3,7 TETRAHYDRO 6H PURIN 6 ONE DERIVATIVE; 3 (2,4 DICHLOROPHENYL) 7 DICYCLOPROPYLMETHYL 8 ETHYL 1 METHYL 1,2,3,7 TETRAHYDRO 6H PURIN 6 ONE; 3 (2,4 DICHLOROPHENYL) 8 ETHYL 7 (4 HEPTYL) 1 METHYL 1,2,3,7 TETRAHYDRO 6H PURIN 6 ONE; 3,7 DIHYDRO 1H PURINE 2,6 DIONE DERIVATIVE; CORTICOTROPIN RELEASING FACTOR ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL CELL; ANXIETY; ARTICLE; CORTICOTROPIN RELEASE; DEPRESSION; DRUG ACTIVITY; DRUG DESIGN; DRUG METABOLISM; DRUG POTENCY; DRUG SYNTHESIS; EVALUATION; HORMONE RECEPTOR INTERACTION; HUMAN; HUMAN CELL; IC 50; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL LINE; CYCLIC AMP; DRUG DESIGN; HUMANS; HYDROXYLATION; INHIBITORY CONCENTRATION 50; MOLECULAR STRUCTURE; PURINES; RATS; RECEPTORS, CORTICOTROPIN-RELEASING HORMONE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 4444224474     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049787k     Document Type: Article

References (44)

1. Guillemin, R.; Rosenburg, B. Humoral hypothalamic control of anterior pituitary: a study with combined tissue cultures. Endocrinology 1955, 57, 599-607.
2. Saffran, M.; Schally, A. V. The release of corticotropin by anterior pituitary tissue in vitro. Can. J. Biochem. Physiol. 1955, 33, 408-415.
3. 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.
4. Rivier, J.; Spiess, J.; Vale, W. Characterization of rat hypothalamic corticotropin-releasing factor. Proc. Natl. Acad. Sci. 1983, 80, 4851-4855.
5. Shibahara, S.; Morimoto, Y.; Furutani, Y.; Notake, M.; Takahashi, H.; Shimizu, S.; Horikawa, S.; Numa, S. Isolation and sequence analysis of the human corticotropin-releasing factor precursor gene. Eur. Mol Biol. Organ. 1983, 2, 775-779.
6. Gilligan, P. J.; Hartig, P. R.; Robertson, D. W.; Zaczek, R. Corticotropin-releasing hormone (CRH) receptors and the discovery of selective non-peptide CRH1 antagonists. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic: San Diego, 1997; Vol. 32, pp 41-50.
7. DeSouza, E. B.; Grigoriadis, D. E. Corticotropin-releasing factor: physiology, pharmacology, and role in central nervous system and immune disorders. In Psychopharmacology; The Fourth Generation of Progress; Bloom, F. E., Kupfer, D. J., Eds.; Raven: New York, 1995; pp 505-517.
8. 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.
9. 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.
10. Perrin, M. H.; Donaldson, C. J.; Chen, R.; Lewis, K. A.; Vale, W. W. Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor. Endocrinology 1993, 733, 3058-3061.
11. Kemp, C. F.; Woods, R. J.; Lowry, P. J. The corticotrophin-releasing factor-binding protein: an act of several parts. Peptides 1998, 19, 1119-1128.
12. Lovenburg, T. W.; Liaw, C. W.; Grigoriadis, D. E.; Clevenger, W.; Chalmers, D. T.; DeSouza, 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.
13. Chalmers, D. T.; Lovenberg, T. W.; DeSouza, E. B. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J. Neurosci. 1995, 15, 6340-6350.
14. Primus, R. J.; Yevich, E.; Baltazer, C.; Gallager, D. W. Autoradiographic localization of CRF1 and CRF2 binding sites in adult rat brain. Neuropsychopharmacology 1997, 17, 308-316.
15. 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 and references therein.
16. Nemeroff, C. B.; Widerlov, E.; Bissette, G.; Wallens, H.; Karlsson, I.; Eklund, K.; Kilts, C. D.; Loosen, P. T.; Vale, W. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984, 226, 1342-1344.
17. Owens, M. J.; Nemeroff, C. B. Physiology and pharmacology of corticotropin-releasing factor. Pharmacol. Rev. 1991, 43, 425-473.
18. Banki, C. M.; Bisette, G.; Arato, M.; O'Conner, L.; Nemeroff, C. B. CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am. J. Psychiatry 1987, 144, 873-877.
19. Zobel, A. W.; Nickel, T.; Künzel, 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.
20. Banki, C. M.; Karmasci, L.; Bissette, G.; Nemeroff, C. B. Cerebrospinal fluid neuropeptides in mood disorder and dementia. J. Affect. Disord. 1992, 25, 39-45.
21. Koob, G. F.; Heinrichs, S. C.; Pich, E. M.; Menzaghi, F.; Baldwin, H.; Miczek, K.; Britton, K. T. The role of corticotropin-releasing factor in behavioral responses to stress. In Corticotropin-Releasing Factor, Ciba Foundation Symposium 172; Chadwick, D. J., Marsh, J., Ackrill, K., Eds.; J. Wiley and Sons: Chicester, 1993; pp 277-291.
22. Webster, E. L.; Torpy, D. J.; Elenkov, I. J.; Chrousos, G. P. Corticotropin-releasing hormone and inflammation. Ann. N. Y. Acad. Sci. 1998, 840, 21-32.
23. Chrousos, G. P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. New Engl. J. Med. 1995, 332, 1351-1362.
24. Gulyas, J.; Rivier, C.; Perrin, M. Koerber, S. C.; Sutgton, S.; Corrigan, A.; Lahrichi, S. L.; Craig, A. G.; Vale, W.; River, J. Potent, structurally constrained agonists and competitive antagonists of corticotropin-releasing factor. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10575-10579.
25. Chen, Y. L.; Mansbach, R. S.; Winter, S. M.; Brooks, E.; Collins, J.; Corman, M. L.; Dunaiskis, A. R.; Faraci, W. S.; Gallaschun, R. J.; Schmidt, A.; Schultz, D. W. Synthesis and oral efficacy of a 4-(butylethylamino)pyrrolo[2,3- d]pyrimidine: a centrally active corticotropin-releasing factor1 receptor antagonist. J. Med. Chem. 1997, 40, 1749-1754.
26. Mansbach, R. S.; Brooks, E. N.; Chen, Y. L. Antidepressant-like effects of CP-154526, a selective CRF1 receptor antagonist. Eur. J. Pharmacol. 1997, 323, 21-26.
27. Arborelius, L.; Skelton, K. H.; Thrivikraman, K. V.; Plotsky, P. M.; Schulz, D. W.; Owens, M. J. Chronic administration of the selective corticotropin-releasing factor 1 receptor antagonist CP-154,526: behavioral, endocrine and neurochemical effects in the rat. J. Pharmacol. Exp. Ther. 2000, 294, 588-597.
28. Keller, P. A.; Elfick, L.; Garner, J.; Morgan, J.; McCluskey, A. Corticotropin releasing hormone: therapeutic implications and medicinal chemistry developments. Bioorg. Med. Chem. 2000, 8, 1213-1223.
29. 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.
30. Merlos, M.; Gomez, I.; Vericat, M. L.; Bartroli, J.; Garcia-Rafanell, J.; Forn, J. Structure-activity relationships in a series of xanthine derivatives with antibronchoconstrictory and bronchodilatory activities. Eur. J. Med. Chem. 1990, 25, 653-658.
31. Papesh, V.; Schroeder, E. F. Synthesis of 1-mono- and 1,3-disubstituted 6-aminouracils. Diuretic activity. J. Org. Chem. 1951, 16, 1879-1890.
32. Kramer, G. L.; Garst, J. E.; Mitchel, S. S.; Wells, J. N. Selective inhibition of cyclic nucleotide phosphodiesterases by analogues of 1-methyl-3-isobutylxanthine. Biochemistry 1977, 16, 3316-3321.
33. Garst, J. E.; Kramer, G. L.; Wu, Y. J.; Wells, J. N. Inhibition of separated forms of phosphodiesterases from pig coronary arteries by uracils and by 7-substituted derivatives of 1-methyl-3-isobutylxanthine. J. Med. Chem. 1976, 19, 499-503.
34. Mitsunobu, O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis 1981, 1-28.
35. 2 was bonded via a primary carbon, e.g. 12m, the reaction was carried out at room temperature or slightly above to provide the desired product as a single regioisomer, at higher temperatures a mixture of regioisomers was observed.
36. 2 contained a cyclopropyl group next to the leaving group, only the Mitsunobu conditions furnished the desired product.
37. Ohsaki, T.; Kuriki, T.; Ueda, T.; Sakakibara, J. Studies on xanthine derivatives. II. Synthesis of 1,2,3,7-tetrahydro-6H-purin-6-ones from xanthine hydrolyzates. Chem. Pharm. Bull. 1986, 34, 36-50.
38. Wolfe, J. P.; Buchwald, S. L. Scope and limitations of the Pd/BINAP-catalyzed animation of aryl bromides. J. Org. Chem. 2000, 65, 1144-1157.
39. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. Simple, efficient catalyst system for the palladium-catalyzed animation of aryl chlorides, bromides, and triflates. J. Org. Chem. 2000, 65, 1158-1174.
40. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. Room-Temperature Palladium-Catalyzed Amination of Aryl Bromides and Chlorides and Extended Scope of Aromatic C-N Bond Formation with a Commercial Ligand. J. Org. Chem. 1999, 64, 5575-5580.
41. Lam, P. S. Y.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Copper promoted aryl/saturated heterocyclic C-N bond cross-coupling with arylboronic acid and arylstannane. Synthesis 2000, 674-676.
42. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. New N- and O-arylation with phenylboronic acids and cupric acetate. Tetrahedron Lett. 1998, 39, 2933-2936.
43. Gilligan, P. J.; He, L.; Culp, S.; Fitzgerald, L.; Tam, S. W.; Wong, Y. N. Structure-activity studies on 4-substituted-2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists. Bioorg. Med. Chem. 1999, 7, 2321-2328.
44. The agonist and antagonist properties of 12d and 12j were determined by ACTH release as described in Zhang, G.; Huang, N.; Li, Y.-W.; Qi, X.; Marshall, A. P.; Yan, X.-X.; Hill, G.; Rominger, C.; Prakash, S. R.; Bakthavatchalam, R.; Rominger, D. H.; Gilligan, P. J.; Zaczek, R. J. Pharmacol. Exp. Ther. 2003, 305, 57-69.