Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity

Journal of Medicinal Chemistry

Volumn 40, Issue 14, 1997, Pages 2196-2210

  Ahn, Ho Sam ^a   Bercovici, Ana ^a   Boykow, George ^a   Bronnenkant, Alan ^a   Chackalamannil, Samuel ^a   Chow, Jason ^a   Cleven, Renee ^a   Cook, John ^a   Czarniecki, Michael ^a   Domalski, Carol ^a   Fawzi, Ahmad ^a   Green, Michael ^a   Gündes, Asli ^a   Ho, Ginny ^a   Laudicina, Malvina ^a   Lindo, Neil ^a   Ma, Ke ^a   Manna, Mahua ^a   McKittrick, Brian ^a   Mirzai, Bita ^a   Nechuta, Terry ^a   Neustadt, Bernard ^a   Puchalski, Chester ^a   Pula, Kathryn ^a   Silverman, Lisa ^a   Smith, Elizabeth ^a   Stamford, Andrew ^a   Tedesco, Richard P ^a   Tsai, Hsingan ^a   Tulshian, Deen ^a   Vaccaro, Henry ^a   Watkins, Robert W ^a   Weng, Xiaoyu ^a   Witkowski, Joseph T ^a   Xia, Yan ^a   Zhang, Hongtao ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [6 CHLORO 4 (3,4 METHYLENEDIOXYBENZYLAMINO) 2 QUINAZOLINYL] 4 PIPERIDINECARBOXYLIC ACID; 2 (4 BIPHENYLYLMETHYL) 5,6A,7,8,9,9A HEXAHYDRO 5 METHYL 3 (PHENYLMETHYL)CYCLOPENT[4,5]IMIDAZO[2,1 B]PURIN 4(3H) ONE; 2 (CYCLOHEXYLMETHYL) 5,6A,7,8,9,9A HEXAHYDRO 5 METHYLCYCLOPENT[4,5]IMIDAZO[2,1 B]PURIN 4(3H) ONE; 2 (PHENYLMETHYL) 5,6A,7,8,9,9A HEXAHYDRO 5 METHYLCYCLOPENT[4,5]IMIDAZO[2,1 B]PURIN 4(3H) ONE; 2 HEXYL 5,6A,7,8,9,9A HEXAHYDRO 5 METHYLCYCLOPENT[4,5]IMIDAZO[2,1 B]PURIN 4(3H) ONE; 5' METHYL 2' (CYCLOPENTYLMETHYL)SPIRO(CYCLOPENTANE 1,7'(8'H) [3H]IMIDAZO[2,1 B]PURIN) 4'(5'H) ONE; 5' METHYL 2' (PHENYLMETHYL)SPIRO(CYCLOPENTANE 1,7'(8'H) [3H]IMIDAZO[2,1 B)PURIN 4'(5'H) ONE; CYCLIC GMP; PHOSPHODIESTERASE I; UNCLASSIFIED DRUG; VINPOCETINE; ZAPRINAST;

ANIMAL MODEL; ANTIHYPERTENSIVE ACTIVITY; ARTICLE; BLOOD VESSEL REACTIVITY; DRUG MECHANISM; HYPERTENSION; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; SPONTANEOUSLY HYPERTENSIVE RAT; STRUCTURE ACTIVITY RELATION;

3',5'-CYCLIC-GMP PHOSPHODIESTERASE; 3',5'-CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ADMINISTRATION, ORAL; ANIMALS; ANTIHYPERTENSIVE AGENTS; BLOOD PRESSURE; GUANINE; INDICATORS AND REAGENTS; ISOENZYMES; KINETICS; MAGNETIC RESONANCE SPECTROSCOPY; MOLECULAR STRUCTURE; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; PYRROLES; RATS; RATS, INBRED SHR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 15444346896     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9608467     Document Type: Article

References (21)

1. Sonnenburg, W. K.; Beavo, J. A. Cyclic GMP and Regulation of Cyclic Nucelotide Hydrolysis Adv. Pharmacol. 1994, 26, 87-114.
2. Warner, T. D.; Mitchell, J. A.; Sheng, H.; Murad, F. Effects of Cyclic GMP on Smooth Muscle Relaxation. Adv. Pharmacol. 1994, 26, 171-194.
3. Sybertz, E. J.; Czarniecki, M.; Ahn, H.-S. cGMP Phosphodiesterase Inhibition: A New Mechanism for the Discovery of Therapeutic Agents. Curr. Pharm. Des. 1995, 1, 373-390.
4. Beavo, J. A. Cyclic Nucleotide Phosphodiesterases: Functional Implications of Multiple Isoforms. Physiol. Rev. 1995, 75, 725-748.
5. Czarniecki, M.; Sybertz, E. J.; Ahn, H.-S. Inhibitors of Type I and V Phosphodiesterase: Elevation of cGMP as a Therapeutic Strategy. Annu. Rep. Med. Chem. 1996, 31, 61-70.
6. Ahn, H.-S.; Crim, W.; Romano, M.; Sybertz, E.; Pitts, B. Effects of selective Inhibitors on Cyclic Nucleotide Phosphodiesterases of Rabbit Aorta. Biochem. Pharmacol. 1989, 38, 3331-3339.
7. Saeki, T.; Adachi, H.; Takase, Y.; Yoshitake, S.; Souda, S.; Saito, I. A Selective Type V Phosphodiesterase Inhibitor, E4021, Dilates Porcine Large Coronary Artery. J. Pharmacol. Exp. Ther. 1995, 272, 825-831.
8. McMahon, E. G.; Palomo, M. A.; Mehta, P.; Olins, G. M. Depressor and Natriuretic Effects of M&B 22,948, a Guanosine Cyclic 3′,5′-Monophosphate-Selective Phosphodiesterase. J. Pharmacol. Exp. Ther. 1989, 251, 1000-1005.
9. Fenn, M. D.; Lister, J. H. Purine Studies. XXIII Confonnational Aspects of N-(6-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)formamides and Related N-Benzyl Derivatives. Aust. J. Chem. 1980, 33, 1611-1617.
10. The (-)-trans-2-aminocyclopentanol can be prepared in >96% ee using the method of Overman, L. E.; Sugai, S. A Convenient Method for Obtaining trans-2-Aminocyclohexanol and trans-2-Aminocyclopentanol in Enantiomerically Pure Form. J. Org. Chem. 1985, 50, 4154-4155.
11. In the early phases of this project we compared the activity of the enantiomers of compounds closely related to the structures disclosed in this study. In all cases examined the (+) isomer was about 10-fold more active in a preparation of PDE1 than the (-) isomer. Since the assay protocol used at that time was substantially different from that reported here, those results cannot be directly compared with the results reported in this manuscript. These results, however, led us to continue to make the (+) isomers in this study.
12. Vemulapalli, S.; Watkins, R. W.; Chintala, M.; Davis, H.; Ahn, H.-S.; Fawzi, A.; Tulshian, D.; Chiu, P.; Chatterjee, M.; Lin, C.-C.; Sybertz, E. J. Antiplatelet and Antiproliferative Effects of SCH 51866, a Novel Type 1 and Type 5 Phosphodiesterase Inhibitor J. Cardiovasc. Pharmacol. 1996, 28, 862-869.
13. Takase, Y.; Watanabe, N.; Matsui, M.; Ikuta, H.; Kimura, T.; Saeki, T.; Adachi, H.; Tokumura, T.; Mochida, H.; Akita, Y.; Souda, S. South African Patent 927465, 1992.
14. Neustadt, B.; Lindo, N.; McKittrick, B. U.S. Patent 5393755, 1995.
15. De Meester, J. W. G.; van der Plas, H. C.; Middelhoven, W. J. The Oxidation of 6-and 7-Aryl-4(3H)-pteridinones by Immobilized Arthrobacter M-4 Cells Containing Xanthine Oxidase J. Heterocycl. Chem. 1987, 24, 441-451.
16. Thompson, W. J.; Brooker, G.; Appleman, M. M. Assay of Cyclic Nucleotide Phosphodiesterases with Radioactive Substrates. Methods Enzymol. 1974, 38, 205-212.
17. Sonnenburg, W. K.; Mullaney, P. J.; Beavo, J. A. Molecular Cloning of a Cyclic GMP Stimulated Cyclic Nucleotide Phosphodiesterase cDNA. J. Biol. Chem. 1991, 266, 17655-17661.
18. Harrison, S. A.; Reifsnyder, D. H.; Gallis, B.; Cadd, G. G.; Beavo, J. A. Isolation and Characterization of Bovine Cardiac Muscle cGMP Inhibited Phosphodiesterase: A Receptor for New Cardiotonic Drugs. Mol. Pharmacol. 1986, 29, 506-514.
19. Thompson, W. J.; Shen, C.-C.; Strada, S. J. Preparation of Dog Kidney High-affinity cAMP Phosphodiesterase. Methods Enzymol. 1988, 159, 760-772.
20. Thomas, M. K.; Francis, S. H.; Corbin, J. D. Characterization of a Purified Bovine Lung cGMP Binding cGMP Phosphodiesterase. J. Biol. Chem. 1990, 265, 14964-14970.
21. Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; Gold, E. H.; Sommer, J. A.; Brown, A. D.; Chiu, P. J. S.; Moran, R.; Sybertz, E. J.; Baum, T. Synthesis and Pharmacological Activity of Angiotensin Converting Enzyme Inhibitors: N-(Mercaptoacyl)-4-substituted-(s)-proline. J. Med. Chem. 1988, 31, 875-885.