Novel potent and efficacious nonpeptidic urotensin II receptor agonists

Journal of Medicinal Chemistry

Volumn 49, Issue 7, 2006, Pages 2232-2240

  Lehmann, Fredrik ^a   Pettersen, Anna ^a   Currier, Erika A ^c   Sherbukhin, Vladimir ^b   Olsson, Roger ^b   Hacksell, Uli ^c   Luthman, Kristina ^a  

^a UNIVERSITY OF GOTHENBURG   (Sweden)

^b ACADIA Pharmaceuticals AB   (Sweden)

^c ACADIA PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (4 CHLOROPHENYL) 3 DIMETHYLAMINOPROPYL 2 METHYLBENZOATE; 6,7 DIMETHYL 3 (4 CHLOROPHENYL) 3 (2 DIMETHYLAMINOETHYL)ISOCHROMANONE; AC 7954; FL 68; ISOCHROMAN DERIVATIVE; N [1 (4 CHLOROPHENYL) 3 (DIMETHYLAMINO)PROPYL] 4 PHENYLBENZAMIDE OXALATE; UNCLASSIFIED DRUG; UROTENSIN II;

ARTICLE; DIASTEREOISOMER; DRUG CONFORMATION; DRUG EFFICACY; DRUG POTENCY; DRUG SYNTHESIS; ENANTIOMER; RING OPENING; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ANIMALS; BENZAMIDES; CRYSTALLOGRAPHY, X-RAY; ESTERS; ETHERS; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; NIH 3T3 CELLS; RECEPTORS, G-PROTEIN-COUPLED; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; UREA;

EID: 33645669146     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm051121i     Document Type: Article

References (38)

1. Dhanak, D.; Neeb, M. J.; Douglas, S. A. Urotensin-II receptor modulators. Annu. Rep. Med. Chem. 2003, 38, 99-110.
2. Doggrell, S. A. Urotensin-II and the cardiovascular system - the importance of developing modulators. Expert Opin. Invest. Drug 2004, 13, 479-487.
3. Douglas, S.; Dhanak, D.; Johns, D. G. From 'gills to pills': urotensin II as a regulator of mammalian cardiorenal function. Trends Pharmacol. Sci. 2004, 25, 76-85.
4. Douglas, S. A. Human urotensin-II as a novel cardiovascular target: 'heart' of the matter or simply a fishy 'tail'? Curr. Opin. Pharmacol. 2003, 3, 159-167.
5. Onan, D.; Hannan, R. D.; Thomas, W. G. Urotensin II: the old kid in town. Trends Endocrinol. Metab. 2004, 15, 175-182.
6. Ong, K. L.; Lam, K. S. L.; Cheung, B. M. Y. Urotensin II: Its function in health and its role in disease. Cardiovasc. Drug Ther. 2005, 19, 65-75.
7. Russell, F. D. Emerging roles of urotensin-II in cardiovascular disease. Pharmacol. Ther. 2004, 103, 223-243.
8. Thanassoulis, G.; Huyhn, T.; Giaid, A. Urotensin II and cardiovascular diseases. Peptides 2004, 25, 1789-1794.
9. Heringlake, M.; Kox, T.; Uzun, O.; Will, B.; Bahlmann, L.; Klaus, S.; Eleftheriadis, S.; Armbruster, F. P.; Franz, N.; Kraatz, E. The relationship between urotensin II plasma immunoreactivity and left ventricular filling pressures in coronary artery disease. Regul. Pept. 2004, 121, 129-136.
10. Douglas, S.; Aiyar, N. V.; Ohlstein, E. H.; Willette, R. N. Human urotensin-II, the most potent mammalian vasoconstrictor identified, represents a novel therapeutic target in the treatment of cardiovascular disease. Eur. Heart J. 2000, 21, 229-237.
11. Bousette, N.; Patel, L.; Douglas, S. A.; Ohlstein, E. H.; Giaid, A. Increased expression of urotensin II and its cognate receptor GPR14 in atherosclerotic lesions of the human aorta. Atherosclerosis 2004, 176, 117-123.
12. Langham, R. G.; Kelly, D. J.; Gow, R. M.; Zhang, Y.; Dowling, J. K.; Thomson, N. M.; Gilbert, R. E. Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy. Am. J. Kidney Dis. 2004, 44, 826-831.
13. Suzuki, S.; Zong, W. Y.; Hirai, M.; Hinokio, Y.; Suzuki, C.; Yamada, T.; Yoshizumi, S.; Suzuki, M.; Tanizawa, Y.; Matsutani, A.; Oka, Y. Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese. Peptides 2004, 25, 1803-1808.
14. Guerrini, R.; Camarda, V.; Marzola, E.; Arduin, M.; Calo, G.; Spagnol, M.; Rizzi, A.; Salvadori, S.; Regoli, D. Structure-activity relationship study on human urotensin II. J. Pept. Sci. 2005, 11, 85-90.
15. Grieco, P.; Rovero, P.; Novellino, E. Recent structure-activity studies of the peptide hormone urotensin-II, a potent vasoconstrictor. Curr. Med. Chem. 2004, 11, 969-979.
16. Lavecchia, A.; Cosconati, S.; Novellino, E. Architecture of the human urotensin II receptor: Comparison of the binding domains of peptide and non-peptide urotensin II agonists. J. Med. Chem. 2005, 48, 2480-2492.
17. Affolter, J.; Webb, D. J. Urotensin II: a new mediator in cardiopulmonary regulation? Lancet 2001, 358, 774-775.
18. Jin, J.; Dhanak, D.; Knight, S. D.; Widdowson, K.; Aiyar, N.; Naselsky, D.; Sarau, H. M.; Foley, J. J.; Schmidt, D. B.; Bennett, C. D. Wang, B.; Warren, G. L.; Moore, M. L.; Keenan, R. M.; Rivero, R. A.; Douglas, S. A. Aminoalkoxybenzyl pyrrolidines as novel human urotensin-II receptor antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 3229-3232.
19. Lehmann, F.; Currier, E. A.; Olsson, R.; Hacksell, U.; Luthman, K. Isochromanone-based urotensin-II receptor agonists. Bioorg. Med. Chem. 2005, 13, 3057-3068.
20. Croston, G. E.; Olsson, R.; Currier, E. A.; Burstein, E. S.; Weiner, D.; Nash, N.; Severance, D.; Allenmark, S. G.; Thunberg, L.; Ma, J. N.; Mohell, N.; O'Dowd, B.; Brann, M. R.; Hacksell, U. Discovery of the first nonpeptide agonist of the GPR14/urotensin-II receptor: 3-(4-chloropheny)-3-(2-(dimethylamino) ethyl)isochroman-1-one (AC-7954). J. Med. Chem. 2002, 45, 4950-4953.
21. Bandini, M.; Cozzi, P. G.; Gazzano, M.; Umani-Ronchi, A. An effective and useful synthesis of enantiomerically enriched arylglycinols. Eur. J. Org. Chem. 2001, 1937-1942.
22. Ritter, J. J.; Minieri, P. P. A new reaction of nitriles. I. Amides from alkenes and mononitriles. J. Am. Chem. Soc. 1948, 70, 4045-4048.
23. When using triethylamine as the base, the quaternary ammonium compound was the major product. The use of DIPEA as the base solved this problem, but made the purification of the products more difficult.
24. Other coupling reagents were also examined; with DCC the formation of product proceeded smoothly, but the products were difficult to purify from the DCU byproduct. When using acid chlorides, more complex mixtures were formed.
25. Takami, A.; Iwakubo, M.; Okada, Y.; Kawata, T.; Odai, H.; Takahashi, N.; Shindo, K.; Kimura, K.; Tagami, Y.; Miyake, M.; Fukushima, K.; Inagaki, M.; Amano, M.; Kaibuchi, K.; Iijima, H. Design and synthesis of Rho kinase inhibitors (I). Bioorg. Med, Chem. 2004, 12, 2115-2137.
26. Bräuner-Osborne, H.; Brann, M. R. Pharmacology of muscarinic acetylcholine receptor subtypes (m1-m5): High throughput assays in mammalian cells. Eur. J. Pharmacol. 1996, 295, 93-102.
27. Burstein, E. S.; Bräuner-Osborne, H.; Spalding, T. A.; Conklin, B. R.; Brann, M. R. Interactions of muscarinic receptors with the heterotrimeric G proteins G(q) and G(12): Transduction of proliferative signals. J. Neurochem. 1997, 68, 525-533.
28. Burstein, E. S.; Spalding, T. A.; Brann, M. R. Pharmacology of muscarinic receptor subtypes constitutively activated by G proteins. Mol. Pharmacol. 1997, 51, 312-319.
29. Spalding, T. A.; Burstein, E. S.; Jorgensen, H. B.; Hilleubanks, D.; Brann, M. R. Pharmacology of a constitutively activated M5 muscarinic receptor. Life Sci. 1995, 56, 1021-1021.
30. An additional set of ester derivatives has been synthesized and tested (4f-4bb). The results are presented in the Supporting Information.
31. Crystallographic data (excluding structure factors) for (+)-51 HCl has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication Nos. CCDC 272185. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Rd., Cambridge CB2 1EZ, UK, (fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
32. Håkansson, M. Labile copper(I) chloride complexes: preparation and handling. Inorg. Synth. 1998, 32, 222-228.
33. Rigaku, CrystalClear, version 1.3, 2000, Rigaku Corporation, Tokyo, Japan.
34. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. Completion and refinement of crystal structures with Sir92. J. Appl. Crystallogr. 1993, 26, 343-350.
35. Sheldrick, G. M., University of Göttingen, Germany, 1997.
36. Farrugia, L. J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr. 1999, 32, 837-838.
37. Farrugia, L. J. ORTEP-3 for Windows - a version of ORTEP-III with a Graphical User Interface (GUI). J. Appl. Crystallogr. 1997, 30.
38. MOETM, the Molecular Operating Environment by Chemical Computing Group, Suite 910-1010 Sherbrooke St., W Montreal, Quebec, Canada H3A 2R7.