De novo design of a novel oxazolidinone analogue as a potent and selective α(1A) adrenergic receptor antagonist with high oral bioavailability

Journal of Medicinal Chemistry

Volumn 43, Issue 15, 2000, Pages 2775-2778

  Lagu, Bharat ^a,c   Tian, Dake ^a   Jeon, Yoon ^a   Li, Chao ^a   Wetzel, John M ^a   Nagarathnam, Dhanapalan ^a   Shen, Quanrong ^a   Forray, Carlos ^a   Chang, Raymond S L ^b   Broten, Theodore P ^b   Ransom, Richard W ^b   Chan, Tsing Bao ^b   O'Malley, Stacey S ^b   Schorn, Terry W ^b   Rodrigues, A David ^b   Kassahun, Kelem ^b   Pettibone, Douglas J ^b   Freidinger, Roger ^b   Gluchowski, Charles ^a  

^a H LUNDBECK A S   (Denmark)

^b MERCK RESEARCH LABORATORIES   (United States)

^c R W JOHNSON PHARMACEUTICAL RES I   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADRENERGIC RECEPTOR BLOCKING AGENT; ALPHA ADRENERGIC RECEPTOR BLOCKING AGENT; DIHYDROPYRIDINE DERIVATIVE; DOXAZOSIN; ISOINDOLE DERIVATIVE; OXAZOLE; OXAZOLIDINONE DERIVATIVE; TAMSULOSIN; TERAZOSIN;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BINDING AFFINITY; CHIRALITY; COLUMN CHROMATOGRAPHY; DIASTEREOISOMER; DOG; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG POTENCY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; NONHUMAN; ORTHOSTATIC HYPOTENSION; PROSTATE HYPERTROPHY; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ADRENERGIC ALPHA-ANTAGONISTS; ANIMALS; AORTA; BINDING, COMPETITIVE; BIOLOGICAL AVAILABILITY; BLOOD PRESSURE; DOGS; HUMANS; MALE; MUSCLE CONTRACTION; MUSCLE, SMOOTH; OXAZOLES; PRESSURE; PROSTATE; RADIOLIGAND ASSAY; RATS; RECEPTORS, ADRENERGIC, ALPHA-1; RECOMBINANT PROTEINS; URETHRA;

EID: 18744437905     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm000085e     Document Type: Article

References (26)

1. Kirby, R. S.; Christmas, T. J. Benign Prostatic Hyperplasia; Gower Medical Publishing: London, England, 1993.
2. Lepor, H. Long-Term Efficacy and Safety of Terazosin in Patients with Benign Prostatic Hyperplasia. Urology 1995, 45, 406-413.
3. Lepor, H.; Kaplan, S. A.; Klimberg, I.; Mobley, D. F.; Fawzy, A.; Gaffney, M.; Ice, K.; Dias, N. Doxazosin for Benign Prostatic Hyperplasia: Long-Term Efficacy and Safety in Hypertensive and Normotensive Patients. The Multicenter Study Group. J. Urol. 1997, 157, 525-530.
4. Chueh, S.; Guh, J.; Chen, J.; Lai, M.; Ko, F.; Teng, C. Inhibition by Tamsulosin of Tension Responses of Human Hyperplastic Prostate to Electrical Field Stimulation. Eur. J. Pharmacol. 1996, 305, 177-180.
5. 1c Subtype. Mol. Pharmacol. 1994, 45, 703-708.
6. 2+ Channel Antagonist Niguldipine. J. Med. Chem. 1995, 38, 1579-1581.
7. 1A Antagonist. Utilization of a Rapid Screening Method to Obtain Pharmacokinetic Parameters. In Integration of Pharmaceutical Discovery and Development: Case Studies; Borchardt et al., Eds.; Plenum Press: New York, 1998; pp 423-443.
8. 1a Adrenoceptor Antagonist for the Symptomatic Treatment of Benign Prostatic Hyperplasia. J. Med. Chem. 1997, 40, 3141-3143.
9. 1a Adrenoceptor Selective Antagonists: Structure-Activity Relationships of Dihydropyrimidinones. J. Med. Chem. 1999, 42, 4764-4777.
10. 1a Adrenoceptor Selective Antagonists: Approaches to Eliminate Opioid Agonist Metabolites via Modification of Linker and 4-Methoxycarbonyl-4-phenylpiperidine Moiety. J. Med. Chem. 1999, 42, 4778-4793.
11. H. Selnick, J. Barrow, Merck Research Laboratories, unpublished results.
12. Ding, C. Z. A Convenient Diastereoselective Synthesis of β-Aryl-β-Amino Alcohols. Tetrahedron Lett. 1996, 37, 945-948.
13. D = -30.8 (c = 0.20, acetone)}, respectively.
14. The absolute and relative stereochemistry of 3 was confirmed by a combination of NOE studies and an alternate synthesis from (S)-(+)-methyl lactate. The details will be published elsewhere.
15. 1b Adrenergic Receptor Antagonist. J. Med. Chem. 1998, 41, 1205-1208.
16. 3H]-Nitrendipine, to Guinea-Pig Ileal Smooth Muscle. J. Pharmacol. Exp. Ther. 1983, 225, 291-309.
17. 2b-Adrenergic Receptor. Mol. Pharmacol. 1990, 38, 681-688.
18. 3H]-Mepyramine Binding of Brain Membranes. J. Neurochem. 1979, 32, 1653-1663.
19. 3H-Tiotidine to Histamine H2 Receptors in Guinea Pig Cerebral Cortex. Nature 1983, 304, 65-67.
20. 1a Receptor. Nature 1988, 335, 358-360.
21. 1dβ. Proc. Natl. Acad. Sci. U.S.A. 1992, 3630-3634.
22. 3H]-Ketanserin Label Two Affinity States of the Cloned Human 5-Hydroxytryptamine2 Receptor. Mol. Pharmacol. 1990, 38, 604-609.
23. Data generated by Panlabs, Bothell, WA.
24. For the description of the protocols for the in vitro and in vivo pharmacological experiments, please see ref 9.
25. 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.
26. Piascik, M. T.; Guarino, R. D.; Smith, M. S.; Soltis, E. E.; Saussy, S. S.; Perez, D. M. The Specific Contribution of the Novel Alpha-1D Adrenoceptor to the Contraction of Vascular Smooth Muscle. J. Pharmacol. Exp. Ther. 1995, 275, 1583-1589.