Identification of a dihydropyridine as a potent α(1a) adrenoceptor- selective antagonist that inhibits phenylephrine-induced contraction of the human prostate

Journal of Medicinal Chemistry

Volumn 41, Issue 14, 1998, Pages 2643-2650

  Wong, Wai C ^a   Chiu, George ^a,c   Wetzel, John M ^a   Marzabadi, Mohammad R ^a   Nagarathnam, Dhanapalan ^a   Wang, Diana ^a,d   Fang, James ^a,f   Miao, Shou Wu ^a,e   Hong, Xingfang ^a,e   Forray, Carlos ^a   Vaysse, Pierre J J ^a   Branchek, Theresa A ^a   Gluchowski, Charles ^a,g   Tang, Rui ^b   Lepor, Herbert ^b  

^a H LUNDBECK A S   (Denmark)

^b NEW YORK UNIVERSITY   (United States)

^c FMC CORPORATION   (United States)

^d YALE UNIVERSITY   (United States)

^e MERCK RESEARCH LABORATORIES   (United States)

^f NOVARTIS PHARMA AG   (Switzerland)

^g RiboGene Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 DIHYDRO 3 (METHOXYCARBONYL) 2,6 DIMETHYL 4 (4 NITROPHENYL) 5 [[3 (4,4 DIPHENYLPIPERIDIN 1 YL)PROPYL]AMINOCARBONYL]PYRIDINE; 5 (AMINOCARBONYL) 1,4 DIHYDRO 2,6 DIMETHYL 4 (4 NITROPHENYL) 3 [[3 (4,4 DIPHENYLPIPERIDIN 1 YL)PROPYL]AMINOCARBONYL]PYRIDINE; ALPHA 1A ADRENERGIC RECEPTOR; CALCIUM CHANNEL; DIHYDROPYRIDINE DERIVATIVE; PHENYLEPHRINE; RECEPTOR SUBTYPE; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; CHIRAL CHROMATOGRAPHY; DISSOCIATION CONSTANT; DRUG IDENTIFICATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; PROSTATE HYPERTROPHY; RECEPTOR BINDING; SYNTHESIS;

ADRENERGIC ALPHA-AGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; AGED; AGED, 80 AND OVER; ANIMALS; BRAIN; CALCIUM CHANNELS; HUMANS; MALE; MIDDLE AGED; MUSCLE CONTRACTION; MUSCLE, SMOOTH; PHENYLEPHRINE; PIPERIDINES; PROSTATE; PROSTATIC HYPERPLASIA; PYRIDINES; RATS; RECEPTORS, ADRENERGIC, ALPHA-1;

EID: 15644366034     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980077m     Document Type: Article

References (29)

1. 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.
2. Monda, J. M.; Oesterling, J. E. Medical Management of Benign Prostatic Hyperplasia: An Update. Infect. Urol. 1994, 47-59.
3. Lepor, H. Long-Term Efficacy and Safety of Terazosin in Patients with Benign Prostatic Hyperplasia. Urology 1995, 45, 406-413.
4. 1-Adrenoceptors: Consensus Update. Pharmacol. Rev. 1995, 47, 267-270.
5. Kawabe, K.; Ueno, A.; Takimoto, Y.; Aso, Y.; Kato, H. YM617 Clinical Study Group. Use of an Alpha-1-blocker, YM617, in the Treatment of Benign Prostatic Hypertrophy. J. Urol. 1990, 144, 908-912.
6. Testa, R.; Taddei, C.; Poggesi, E.; Destefani, C.; Cotecchia, S.; Hieble, J. P.; Sulpizio, A. C.; Naselsky, D.; Bergsma, D.; Ellis, C.; Swift, A.; Ganguly, S.; Ruffolo, R. R., Jr.; Leonardi, A. Rec 15/2739 (SB 216,469): A Novel Prostate Selective Alpha-1-adrenoceptor Antagonist. Pharmacol. Commun. 1995, 6, 79-86.
7. 1-Adrenoceptor Antagonists as Treatments for Benign Prostatic Hyperplasia. Exp. Opin. Invest. Drugs 1995, 4 (10), 915-923.
8. 1-Adrenoceptors and Native Tissues. Mol. Pharmacol. 1995, 48, 250-258.
9. 1c Subtype. Mol. Pharmacol. 1994, 45, 703-708.
10. 2+ Channel Antagonist Niguldipine. J. Med. Chem. 1995, 38, 1579-1581.
11. Presented in part: Wong, W. C.; Marzabadi, M. R.; Wetzel, J. M.; Chiu, G.; Nagarathnam, D.; Wang, D.; Hong, X.; Miao, S. W.; Fang, J.; Forray, C.; Vaysse, P. J.-J.; Branchek, T. A.; Gluchowski, C. Design and Synthesis of Dihydropyridines as Selective Antagonists at the Cloned Human au Adrenoceptor. 210th ACS National Meeting, Chicago, IL, Aug 20-24, 1995; MEDI #43.
12. Eisner, U.; Kuthan, J. The Chemistry of Dihydropyridines. Chem. Rev. 1972, 72, 1-42.
13. Gluchowski, C.; Wetzel, J. M.; Chiu, G.; Marzabadi, M. R.; Wong, W. C.; Nagarathnam, D. Dihydropyridines and New Uses Thereof. International Patent Application WO 94/22829, 1994.
14. Oikawa, Y.; Sugano, K.; Yonemitsu, O. Meldrum's Acid in Organic Synthesis. 2. A General and Versatile Synthesis of β-Keto Ester. J. Org. Chem. 1978, 43, 2087-2088.
15. Marzabadi, M. R.; Hong, X.; Gluchowski, C. A Double Protection Strategy for the Synthesis of 3,5-Disubstituted Dihydropyridines. Tetrahedron Lett., in press.
16. Braibante, M. E. F.; Braibante, H. S.; Missio, L.; Andricopulo, A. Synthesis and Reactivity of β-Amino α,β-Unsaturated Ketones and Esters Using K-10 Montmorillonite. Synthesis 1994, 898-900.
17. Kato, T.; Yamanaka, H.; Kawamata, J.; Shimomura, H. Ketene and Its Derivatives. XXVIII. Reaction of β-Aminocrotonamide with Ketene and Diketene. Chem. Pharm. Bull. 1969, 17, 1889-1895.
18. Sato, M.; Ogasawara, H.; Komatsu, Sl.; Kato, T. Synthesis of β-Ketocarboxamide Derivatives Using 2,2-Dimethyl-2H,4H-1,3-dioxin-4-ones. Chem. Pharm. Bull. 1984, 32, 3848-3856.
19. Achiwa, K. 1,4-Dihydropyridine Derivatives and Process for Preparing the Same. European Patent Application EP 474,129, 1992.
20. 2B-Adrenergic Receptor. Mol. Pharmacol. 1990, 38, 681-688.
21. i values were obtained with incubation time of 4 h; shorter incubation time (30 min) led to significantly lower binding affinity. This was not observed for other compounds in the series.
22. 3H]Nitrendipine, to Guinea-Pig Heal Smooth Muscle. J. Pharmacol. Exp. Ther. 1983, 225, 291-309.
23. 2+ Channel Ligands: Structure-Function Relationships of the 1,4-Dihydropyridines. Med. Res. Rev. 1989, 9, 123-180.
24. 1-Adrenoceptor Subtypes in the Human Prostate: Functional and Binding Studies. Br. J. Urol. 1994, 74, 572-578.
25. 1-Adrenoceptors in Human Prostate: Implications for Adrenoceptor Classification. Mol. Pharmacol. 1996, 49, 209-215.
26. 1 -Adrenoceptor Classification. Br. J. Pharmacol. 1997, 121, 1127-1135.
27. 1c-Adrenergic Antagonists and Orthostatic Hypotension in the Rat. FASEB J. 1994, 8, A353.
28. Testa, R.; Guarneri, L.; Angelico, P.; Poggesi, E.; Taddei, C.; Sironi, G.; Colombo, D.; Sulpizio, A. C.; Naselsky, D. P.; Hieble, J. P.; Leonardi, A. Pharmacological Characterization of the Uroselective Alpha-1 Antagonist Rec 15/2739 (SB 216469): Role of the Alpha-1L Adrenoceptor in Tissue Selectivity, Part II. J. Pharmacol. Exp. Ther. 1997, 281, 1284-1293.
29. 1-adrenoceptors in Vascular Smooth Muscle. Br. J. Pharmacol. 1990, 99, 197-201.