Design and synthesis of novel α(1a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones

Journal of Medicinal Chemistry

Volumn 42, Issue 23, 1999, Pages 4764-4777

  Nagarathnam, Dhanapalan ^a,c   Miao, Shou Wu ^a   Lagu, Bharat ^a   Chiu, George ^a   Fang, James ^a   Dhar, T G Murali ^a   Zhang, Jack ^a   Tyagarajan, Sriram ^a   Marzabadi, Mohammad R ^a   Zhang, Fengqi ^a   Wong, Wai C ^a   Sun, Wanying ^a   Tian, Dake ^a   Wetzel, John M ^a   Forray, Carlos ^a   Chang, Raymond S L ^b   Broten, Theodore P ^b   Ransom, Richard W ^b   Schorn, Terry W ^b   Chen, Tsing B ^b   O'Malley, Stacey ^b   Kling, Paul ^b   Schneck, Kathryn ^b   Bendesky, Robert ^b   Harrell, Charles M ^b   Vyas, Kamlesh P ^b   Gluchowski, Charles ^a,d   more..

^a H LUNDBECK A S   (Denmark)

^b MERCK RESEARCH LABORATORIES   (United States)

^c BAYER CORPORATION   (United States)

^d RiboGene Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (3,4 DIFLUOROPHENYL) 6 ETHYL 3,4 DIHYDRO 2(1H) OXO 3,5 PYRIMIDINEDICARBOXYLIC ACID 5 AMIDE 3 [3 (4 METHOXYCARBONYL 4 PHENYL 1 PIPERIDINYL)PROPYL]AMIDE; 5 CARBOXAMIDO 4 ETHYL 1 [N [3 (4 METHOXYCARBONYLPHENYLPIPERIDIN 1 YL)PROPYL]CARBOXAMIDO] 6 (4 NITROPHENYL) 2 OXO 1,2,3,6 TETRAHYDROPYRIMIDINE; 5 CARBOXAMIDO 6 (3,4 DIFLUOROPHENYL) 4 ETHYL 1 [N [3 (4 METHOXYCARBONYL 4 PHENYLPIPERIDIN 1 YL)PROPYL]CARBOXAMIDO] 2 OXO 1,2,3,6 TETRAHYDROPYRIMIDINE; 5 METHOXYCARBONYL 1 [N [3 (4 METHOXYCARBONYL 4 PHENYLPIPERIDIN 1 YL)PROPYL]CARBOXAMIDO] 4 METHYL 6 (4 NITROPHENYL) 2 OXO 1,2,3,6 TETRAHYDROPYRIMIDINE; ALPHA 1A ADRENERGIC RECEPTOR; ALPHA ADRENERGIC RECEPTOR BLOCKING AGENT; DIHYDROPYRIMIDINONE DERIVATIVE; UNCLASSIFIED DRUG;

ADRENERGIC SYSTEM; ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; INTRAVENOUS DRUG ADMINISTRATION; MALE; NONHUMAN; PROSTATE HYPERTROPHY; STRUCTURE ACTIVITY RELATION;

ADRENERGIC ALPHA-ANTAGONISTS; ANIMALS; BINDING, COMPETITIVE; BLOOD PRESSURE; DOGS; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HUMANS; MALE; PROSTATE; PYRIMIDINONES; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, ADRENERGIC, ALPHA-1; STEREOISOMERISM; URETHRA;

EID: 0344146598     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990200p     Document Type: Article

References (39)

1. Kirby, R. S.; Christmas, T. J. Benign Prostatic Hyperplasia; Gower Medical Publishing: London, England, 1993.
2. Geller, J.; Kirschenbaum, A.; Lepor, H.; Levine, A. C. Therapeutic Controversies: Clinical Treatment of Benign Prostatic Hyperplasia. J. Clin. Endocrinol. Metab. 1995, 80, 745-747.
3. Garraway, W. M.; Collins, G. N.; Lee, R. J.; High Prevalence of Benign Prostatic Hypertrophy in the Community. Lancet 1991, 338, 469-471.
4. Kenny, B.; Ballard, S.; Blagg, J. Fox, D. Pharmacological Options in the Treatment of Benign Prostatic Hyperplasia J. Med. Chem. 1997, 40, 1293-1315.
5. Monda, J. M.; Oesterling, J. E. Medical Management of Benign Prostatic Hyperplasia. Infect. Urol. 1994, 47-59.
6. 2+ Channel Antagonist Niguldipine. J. Med. Chem. 1995, 38, 1579-1581.
7. 1a Adrenoceptor Selective Antagonist that Inhibits Phenylephrine-Induced Contraction of the Human Prostate. J. Med. Chem. 1998, 41, 2643-2650.
8. Nagarathnam, D.; Wetzel, J. M.; Miao, S. W.; Marzabadi, M. R.; Chiu, G.; Wong, W. C.; Hong, X.; Fang, J.; Forray, C.; Branchek, T. A.; Heydorn, W. E.; Chang, R. S. L.; Broten, T.; Schorn, T. W.; Gluchowski, C. Design and Synthesis of Novel Alpha-1a Adrenoceptor Selective Dihydropyridine Antagonists for the Treatment of Benign Prostatic Hyperplasia. J. Med. Chem. 1998, 41, 5320-5333.
9. 1c subtype. Mol. Pharmacol. 1994, 45, 703-708.
10. 1c-Adrenergic Antagonists and Orthostatic Hypotension in the Rat. Faseb J. 1994, 8, A353.
11. Lepor, H. Role of Alpha-Adrenergic Blockers in the Treatment of Benign Prostatic Hyperplasia. Prostate Suppl. 1990, 3, 75-84.
12. Jankegt, R. A.; Chapple, C. R. Efficacy and safety of the Alpha-1 Blocker Doxazosin in the Treatment of Benign Prostatic Hyperplasia. Analysis of 5 Studies. Eur. Urol. 1993, 24, 319-325.
13. Lepor, H. Long-Term Efficacy and Safety of Terazosin in Patients with Benign Prostatic Hyperplasia. Urology 1995, 45, 406-413.
14. Kawabe, K.; Ueno, A.; Takimoto, Y.; Aso, Y.; Kato, H.; Use of an Alpha-1 blocker, YM617, in the Treatment of Benign Prostatic Hypertrophy. J. Urol. 1990, 144, 908-912.
15. 1-adrenoceptor in human prostate. Eur. J. Pharmacol. 1997, 331, 39-42.
16. 1-Adrenoceptor Antagonists. J. Med. Chem. 1997, 40, 2674-2687.
17. 1A Antagonist. Utilization of a Rapid Screening Method to Obtain Pharmacokinetic Parameters. In Integration of Pharmaceutical Discovery and Development: Case Studies; Borchardt et al., Ed.; Plenum Press: New York, 1998; pp 423-443.
18. 1a Adrenoceptor Antagonist for the Symptomatic Treatment of Benign Prostatic Hyperplasia. J. Med. Chem. 1997, 40, 3141-3143.
19. Kenny, B. A.; Naylor, A. M.; Carter, A. J.; Read, A. M.; Greengrass, P. M.; Wyllie, M. G. Effects of alpha-1 adrenoceptor antagonists on prostatic pressure and blood pressure in anaesthetized dog. Urology 1994, 44, 52-57.
20. 1-AR) antagonists in dog prostate/blood pressure models. Faseb J. 1996, 10, A425.
21. Atwal, K. S.; Rovnyak, G. C.; Kimball, D. S.; Floyd, D. M.; Moreland, S.; Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K. S.; Malley, M. F. Dihydropyrimidine Calcium Channel Blockers: 2. 3-Substituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic Acid Esters as Potent Mimics of Dihydropyrimidines. J. Med. Chem. 1990, 33, 2629-2635.
22. Atwal, K. S.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg, A.; Gougoutas, J. Z.; Malley, M. F.; Floyd, D. Dihydropyrimidine Calcium Channel Blockers: 2-Heterosubstituted 4-Aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic Acid Esters as Potent Mimics of Dihydropyrimidines. J. Med. Chem. 1990, 33, 1510-1515.
23. Atwal, K. S.; Rovnyak, G. C.; O'Reilly, B. C.; Schwartz, J. Substituted 1,4-Dihydropyrimidines. 3. Synthesis of Selectively Functionalized 2-Hetero-1,4-dihydropyrimidines. J. Org. Chem. 1989, 54, 5898-5907.
24. Wermuth, C. G. The Practice of Medicinal Chemistry; Academic Press: New York, 1996; Chapter 30.
25. Laz, T. M.; Forray, C.; Smith, K. E.; Bard, J. A.; Vaysse, P. J.; Branchek, T. A.; Weinshank, B. L. The rat homologue of the bovine alpha-1c-adrenergic receptor shows the pharmacological properties of the classical alpha-1A subtype. Mol. Pharmacol. 1994, 46, 414-422.
26. 1 receptors in dog will be published elsewhere.
27. Buckner, S. A.; Oheim, K.; Morse, P.; Knepper, S.; Hancock, A. A. Alpha-1-adrenoceptor induced contracility in rat aorta is mediated by the alpha-1D subtype. Eur. J. Pharmacol. 1996, 297, 241-248.
28. 1-Adrenoceptors and Uroselectivity. Prostate 1996, 30, 202-215.
29. Smith, A. P.; Lee, N. M.; Loh, H. H. In Principles of Pharmacology; Munson, P. L., Ed.; Chapman and Hall: New York; pp 399-416.
30. 3H]Nitrendipine, to Guinea-Pig Ileal Smooth Muscle. J. Pharmacol. Exp. Ther. 1983, 225, 291-309.
31. 2b-Adrenergic Receptor. Mol. Pharmacol. 1990, 38, 681-688.
32. 3H]mepyramine binding of brain membranes. J. Neurochem. 1979, 32, 1653-1663.
33. 2 receptors in guinea pig cerebral cortex. Nature 1983, 304, 65-67.
34. Fargin, A.; Raymond, J.; Lohse, M.; Kobilka, B.; Caron, M.; Lefkowitz, R. The genomic clone G-21, which resembles the a-adrenergic receptor sequence, encodes the 5-HT1a receptor. Nature 1988, 335, 358-360.
35. 1Dβ. Proc. Natl. Acad. Sci. U.S.A. 1992, 3630-3634.
36. 3H]-Ketanserin label two affinity states of the cloned human 5-hydroxytryptamine2 receptor. Mol. Pharmacol. 1990, 38, 604-609.
37. Knepper, S. M.; Buckner, S. A.; Brune, M. E.; DeBernardis, J. F.; Meyer, M. D.; Hancock, A. A. A-61603, a potent alpha-1 adrenergic receptor agonist, selective for the alpha-1a receptor subtype. J. Pharmacol. Exp. Ther. 1995, 274, 97-103.
38. 125I]-L-762,459, A Selective Alpha-1A Radioligand, to Rat and Human Tissues. Eur. J. Pharmacol. 1998, 348, 287-295.
39. Arulaksana, O.; Schild, H. O. Some quantitative uses of drug antagonists. Br. J. Pharmacol. 1959, 14, 48-58.