Synthesis of 3-arylpiperazinylalkylpyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as novel, potent, and selective α1-adrenoceptor ligands

Journal of Medicinal Chemistry

Volumn 48, Issue 7, 2005, Pages 2420-2431

  Patanè, Emanuele ^a   Pittalà, Valeria ^a   Guerrera, Francesco ^a   Salerno, Loredana ^a   Romeo, Giuseppe ^a   Siracusa, Maria Angela ^a   Russo, Filippo ^a   Manetti, Fabrizio ^c   Botta, Maurizio ^c   Mereghetti, Ilario ^b   Cagnotto, Alfredo ^b   Mennini, Tiziana ^b  

^a UNIVERSITY OF CATANIA   (Italy)

^b MARIO NEGRI INSTITUTE FOR PHARMACOLOGICAL RESEARCH   (Italy)

^c UNIVERSITY OF SIENA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

3 [2 [4 (2 CHLOROPHENYL)PIPERAZIN 1 YL]ETHYL] 6 (2 CHLOROPHENYL) 1,5 DIHYDROPYRROLO[3,2 D]PYRIMIDINE 2,4 DIONE; 3 [2 [4 (2 CHLOROPHENYL)PIPERAZIN 1 YL]ETHYL] 6 (4 CHLOROPHENYL) 1,5 DIHYDROPYRROLO[3,2 D]PYRIMIDINE 2,4 DIONE; 3 [2 [4 (2 CHLOROPHENYL)PIPERAZIN 1 YL]ETHYL] 6 (4 METHYLPHENYL) 1,5 DIHYDROPYRROLO[3,2 D]PYRIMIDINE 2,4 DIONE; ALPHA 1 ADRENERGIC RECEPTOR; DOPAMINE 1 RECEPTOR; DOPAMINE 2 RECEPTOR; PIPERAZINE DERIVATIVE; PYRROLO[3,2 D]PYRIMIDINE 2,4 DIONE DERIVATIVE; PYRROLOPYRIMIDINE DERIVATIVE; RADIOLIGAND; SEROTONIN 1A RECEPTOR; UNCLASSIFIED DRUG;

ADRENERGIC SYSTEM; ALGORITHM; ARTICLE; BINDING AFFINITY; CHEMICAL STRUCTURE; DOPAMINERGIC SYSTEM; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; LIGAND BINDING; PROTON NUCLEAR MAGNETIC RESONANCE; QUANTITATIVE STRUCTURE ACTIVITY RELATION; SEROTONINERGIC SYSTEM;

ALGORITHMS; ANIMALS; BRAIN; LIGANDS; MALE; MODELS, MOLECULAR; PIPERAZINES; PYRIMIDINES; PYRROLES; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RADIOLIGAND ASSAY; RATS; RECEPTORS, ADRENERGIC, ALPHA-1;

EID: 20244387435     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm040870h     Document Type: Article

References (41)

1. Hieble, J. P.; Bondinell, W. E.; Ruffolo, R. R. α- and β-Adrenoceptors: From the Gene to the Clinic. 1. Molecular Biology and Adrenoceptor Subclassification. J. Med. Chem. 1995, 38, 3415-3444.
2. Ruffolo, R. R., Jr.; Bondinell, W.; Hieble, J. P. α- and β-Adrenoceptors: From the Gene to the Clinic. 2. Structure-Activity Relationships and Therapeutic Applications. J. Med. Chem. 1995, 38, 3681-3716.
3. 1-Adrenoceptor Classification: Sharpening Occam's Razor. Trends Pharmacol. Sci. 1994, 15, 167-170.
4. 1- Adrenoceptors: Consensus Update. Pharmacol. Rev. 1995, 47, 267-270.
5. 1-Adrenoceptor Subtypes. Eur. J. Pharmacol. 1989, 375, 261-276.
6. Flavahan, N. A.; Vanhoutte, P. M. α-Adrenoceptor Subclassification in Vascular Smooth Muscle. Trends Pharmacol. Sci. 1980, 7, 347-349.
7. 1-Adrenoceptors in Vascular Smooth Muscle. Br. J. Pharmacol. 1990, 99, 197-201.
8. Grassi, G. Sympathetic Deactivation as a Goal of Nonpharmacologic and Pharmacologic Antihypertensive Treatment: Rationale and Options. Curr. Hypertens. Rep. 2003, 5, 277-280.
9. Vaughan, E. D. Jr. Medical Management of Benign Prostatic Hyperplasia. Are Two Drugs Better Than One? N. Engl. J. Med. 2003, 349, 2449-2451.
10. 1 Adrenoceptor Subtypes: A Synopsis of Their Pharmacology and Molecular Biology. Drug Dev. Res. 1996, 39, 54-107.
11. Trumpp-Kallmayer, S.; Hoflack, J.; Bruinvels, A.; Hibert, M. Modeling of G-Protein-Coupled Receptors: Application to Dopamine, Adrenaline, Serotonin, Acetylcholine, and Mammalian Opsin Receptors. J. Med. Chem. 1992, 35, 3448-3462.
12. 2-Adrenoceptors. J. Med. Chem. 2001, 44, 2118-2132.
13. 1-Adrenoceptor Antagonists. 5. Pyridazinone-arylpiperazines. Probing the Influence on Affinity and Selectivity of Both ortho-Alkoxy Groups at the Arylpiperazine Moiety and Cyclic Substituents at the Pyridazinone Nucleus. Bioorg. Med. Chem. Lett. 2003, 13, 171-173.
14. 1-Adrenoceptor Antagonists. 6. Structural Optimation of Pyridazinone-Arylpiperazines. Study of the Influence on Affinity and Selectivity of Cyclic Substituents at the Pyridazinone Ring and Alkoxy Groups at the Arylpiperazine Moiety. J. Med. Chem. 2003, 46, 3555-3558.
15. 1D Receptor. Bioorg. Med. Chem. Lett. 2001, 11, 1119-1121.
16. 1 Adrenoceptor Antagonists. J. Med. Chem. 2001, 44, 2403-2410.
17. 1-Adrenoceptor Antagonists. J. Med. Chem. 1998, 41, 3128-3141.
18. 1 Adrenoceptors Ligands. J. Med. Chem. 1991, 34, 1850-1854.
19. Meyer, M. D.; Carrol, W. A. Piperazinyl Pyrimidine Dione Compounds Selective for Adrenoceptors. U.S. 6,153,614, November 28, 2000.
20. Rogers, D.; Hopfinger, A. J. Application of Genetic Function Approximation to Quantitative Structure-Property Relationships. J. Chem. Inf. Comput. Sci. 1994, 34, 854-866.
21. Rogers, D. Some Theory and Examples of Genetic Function Approximation with Comparison to Evolutionary Techniques. In Genetic Algorithms in Molecular Modeling; Devillers, J., Ed.; Academic Press: London, 1996; pp 87-107.
22. Furneaux, R. H.; Tyler, P. C. Improved Synthesis of 3H,5HPyrrolo[3,2-d] pyrimidines. J. Org. Chem. 1999, 64, 8411-8412.
23. Chen, N.; Lu, Y.; Gadamasetti, K.; Hurt, C. R.; Norman, M. H.; Fotsch, C. A Short, Facile Synthesis of 5-Substituted 3-Amino-1H-pyrrole-2-carboxylates. J. Org. Chem. 2000, 65, 2603-2605.
24. Norman, M. H.; Chen, N.; Han, N.; Liu, L.; Hurt, C. R.; Fotsch, C. H.; Jenkins, T. J.; Moreno, O. A. Bicyclic Pyridine and Pyrimidine Derivatives as Neuropeptide Y Receptor Antagonists. WO 9940,091, August 12, 1999.
25. Norman, M. H.; Chen, N.; Chen, Z.; Fotsch, C.; Hale, C.; Han, N.; Hurt, R.; Jenkins, T.; Kincaid, J.; Liu, L.; Lu, Y.; Moreno, O.; Santora, V. J.; Sonnenberg, J.; Karbon, W. Structure-Activity Relationships of a Series of Pyrrolo[3,2-d]pyrimidine Derivatives and Related Compounds as Neuropeptide Y5 Receptor Antagonists. J. Med. Chem. 2000, 43, 4288-4312.
26. 1-Adrenoceptor. Eur. J. Pharmacol. 1995, 272, R5-R6.
27. 1A Receptor in Rat and Guinea Pig Hippocampal Membranes. Eur. J. Pharmacol. 1987, 137, 293-294.
28. Russell, R. K.; Press: J. B.; Rampulla, R. A.; McNally, J. J.; Falotico, R.; Keiser, J. A.; Bright, D. A.; Tobia, A. Thiopene Systems. 9. Thienopyrimidinedione Derivatives as Potential Anthypertensive Agents. J. Med. Chem. 1988, 31, 1786-1793.
29. 1- Adrenoceptors. Farmaco 1995, 6, 471-477.
30. 2 (version 4.8.1), Catalyst (version 4.8), and InsightII (version 2000.1) softwares are distributed by Accelrys, Scranton Road, San Diego, CA.
31. Fan, Y.; Shi, L. M.; Kohn, K. W.; Pommier, Y.; Weinstein, J. N. Quantitative Structure-Antitumor Activity Relationships of Camptothecin Analogues: Cluster Analysis and Genetic Algorithm-Based Studies. J. Med. Chem. 2001, 44, 3254-3263.
32. Gokhale, V. M.; Kulkarni, V. M. Understanding the Antifungal Activity of Terbinafine Analogues Using Quantitative Structure-Activity Relationship (QSAR) Models. Bioorg. Med. Chem. 2000, 8, 2487-2499.
33. Lee, K. W.; Briggs, J. M. Comparative Molecular Field Analysis (CoMFA) Study of Epothilones-Tubulin Depolymerization Inhibitors: Pharmacophore Development Using 3D QSAR Methods. J. Comput.-Aided Mol. Des. 2001, 15, 41-55.
34. Wang, S.; Sakamuri, S.; Enyedy, I. J.; Kozikowski, A. P.; Zaman, W. A.; Johnson, K. M. Molecular Modeling, Structure-Activity Relationships and Functional Antagonism Studies of 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3- piperidyl 4-Methylphenyl Ketones as a Novel Class of Dopamine Transporter Inhibitors. Bioorg. Med. Chem. 2001, 9, 1753-1764.
35. Internal or standard cross-validation in GFA encompasses only the optimization of regression coefficients but does not encompass the optimization of the choice of molecular descriptors.
36. Kier, L. B.; Hall, L. H. An Electrotopological-State Index for Atoms in Molecules. Pharm. Res. 1990, 7, 801-807.
37. Hall, L. H.; Mohney, B.; Kier, L. B. The Electrotopological State: An Atom Index for QSAR. Quant. Struct.-Act. Relat. 1991, 10, 43-51.
38. Procedures involving animals and their care were conducted in conformity with the institutional guidelines that are in compliance with national (D.L. n. 116, G.U., Suppl. 40, February 18, 1992) and international laws and policies (EEC Council Directive 86/609, OJ L 358, 1, December 12, 1987; Guide for the Care and Use of Laboratory Animals, U.S. National Research Council, 1996).
39. Caccia, S.; Confalonieri, S.; Guiso, G.; Bernasconi, P.; Cagnotto, A.; Skorupscka, M.; Mennini, T. Brain Uptake and Distribution of the Potential Memory Enhancer CL 275,838 and Its Main Metabolites in Rats: Relationship between Brain Concentrations and in Vitro Potencies on Neurotransmitter Mechanisms. Psychopharmacology 1994, 115, 502-508.
40. De Lean, K. W.; Munson, P. J.; Rodbard, D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am. J. Physiol. 1978, 235, E97-E102.
41. 50) of an Enzymatic Reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.