Document Type : Original Article


1 Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, 21955, Saudi Arabia.

2 Glocal School of Pharmacy, Glocal University, Mirzapur Pole, Saharanpur, Uttar Pradesh, India


Pyridazine derivatives are significant bioactive molecules having wide range of biological activities. Phosphodiesterase (PDE) enzymes, particularly PDE-III, PDE-IV, and PDE-V are inhibited by some pyridazine compounds. PDEs are cyclic nucleotide-hydrolyzing enzymes that regulate intracellular levels of the secondary messengers (cAMP and cGMP), cell activities and their specific inhibitory effects for the treatment of various disorders. PDE isoenzyme selective inhibitors include PDE-III inhibitors for congestive heart failure (CHF), PDE-IV inhibitors for inflammatory disorders, and PDE-V inhibitors for erectile dysfunction. The PDE-V inhibitor should be utilized in pulmonary hypertension. In this article, study the PDE activities of various pyridazine compounds.

Graphical Abstract

Pyridazine derivatives act as phosphodiesterase-III, IV, and V Inhibitors



Phosphodiesterase (PDE) was firstly isolated from rat brains in 1972, and a series of drugs were quickly recognized to especially inhibit it in the brain and other tissues [1]. Selective PDE inhibitor medicinal potential was first expected in 1977 [2,3]. PDE inhibitor inhibits the PDE enzyme, avoiding the PDE subtype from inactivating the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDEs are a group of enzymes that hydrolyze cyclic nucleotides, regulating intracellular levels of the secondary messengers and cell activities. The recognition of eleven (I-XI) isoenzymes, and their function at the cellular and molecular level, has stimulated the development of isoenzyme-specific inhibitors for the treatment of various disorders.

PDE isoenzyme selective inhibitors include the PDE-III inhibitors for congestive heart failure (CHF) and their use in improving quality of life in patients with intermittent claudication [4], PDE-IV inhibitors for inflammatory diseases, and PDE-V inhibitors for erectile dysfunction [5]. PDE inhibitors are selectively dangerous to cancer cells because distinct PDE isoenzymes are overexpressed in different tumor cells. PDE inhibitors work with already existing anticancer drugs and might be used in the cancer treatment plan.

In recent years, the activities of pyridazine derivatives have grown widely. These derivatives have a wide range of pharmacological properties, such as cardiovascular and cardiotonic agents (zardaverine, imidazole, bemoradan, indolindan, and pimobendan), vasodilator, antiplatelet, antidepressant, antihypertensive, antithrombotic, antifungal, antibacterial, antimicrobial, analgesic, anti-inflammatory, antifeedant, anticancer, diuretics, anti-HIV, and other pharmacological properties [7-18].

Nonselective phosphodiesterase (PDE) inhibitors

Nonselective adenosine receptor antagonists and competitive nonselective PDE inhibitors enhance intracellular cAMP, activate PKA, inhibit TNF- and leukotriene production, and reduce inflammation and innate immunity. In the pursuit of molecules with improved selectivity for PDE enzyme or adenosine receptor subtypes, several synthetic xanthine derivatives have been formed [19-22].

Phosphodiesterase (PDE) Enzyme Inhibitors

The effects of the diuretics 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) (1) and its 4'-hydroxy derivative [DS-511(4'-OH)] on the ADH-cyclic AMP system in rat renal medulla slices have been examined. The basal levels of slices cAMP are unaffected by these substances. After preincubation with DS-511 or DS-511-(4'-OH) in the presence of theophylline, the making of cAMP was prevented, but it was restored after washing the slices. Higher levels were required to block etacrynic acid. Hydrochlorothiazide and furosemide had no effect. DS-511(4'-OH) reduced the effect of cAMP-PDE in the medullary homogenate. The diuretic action of DS-511 was mediated in part by its suppression of the ADH-cyclic AMP pathway [23].

In vitro, theophylline and three lipolytic compounds, 2,5-bis(2-chloro ethylsulfonyl)-pyrrole-3,4-dicarbonitrile (substituted pyrrole), 2,4-diamino-6-butoxy-s-triazine (substituted triazine), and 2,3-dihydro-5,6-dimethyl-3-oxo-4-pyridazine carbonitrile (substituted pyridazine) (2), stimulated basal lipolysis in adipose tissue. They also promoted an increase in the release of free fatty acids (FFAs), but not glycerol, from adipose tissue when the adrenaline had already driven lipolysis to its highest. The cyclic AMP PDE and the change of [1-(14)C]glucose to (14)CO were likewise inhibited by these four drugs. The accumulation of FFAs as a result of hindered re-esterification was confirmed. After oral or intraperitoneal (i.p.) injection, the substituted pyridazine and triazine, but not the pyrrole, raised plasma FFAs in rats [24].

Phosphodiesterase (PDE)-III selective inhibitors

Clinically, PDE-III antagonists are used to treating heart dysfunction. These drugs enhance cardiac activity by simulating sympathetic stimulation. Intermittent claudication is also treated with this drug. PDE-III is also known as the cGMP-inhibited PDE [25-27].

Phosphodiesterase (PDE)-III Inhibitors and Pyridazine Derivatives

A sequence of 6-(4-(substituted-amino)phenyl)-4,5-dihydro-pyridazin-3(

  1. References 

    1. Uzunov, B. Weiss., Biochim. Biophys. Acta, 1972, 284, 220-226. [Crossref], [Google Scholar], [Publisher]
    2. Weiss., Adv. Cycl. Nucleotide Res., 1975, 5, 195-211. [PMID: 165666 ], [Google Scholar], [Publisher]
    3. M. Essayan., J. Allergy. Clin. Immunol., 2001, 108, 671–680. [Crossref], [Google Scholar], [Publisher]
    4. P. Reilly, E.R. Mohler., Ann. Pharmacother., 2001, 35, 48-56. [Crossref], [Google Scholar], [Publisher]
    5. Victoria, S. Domenico, P. Clive., Br. J. Pharmacol., 2006, 147, S252–S257.[Crossref], [Google Scholar], [Publisher]
    6. R. Wilkins, J. Wharton, F. Grimminger, H.A. Ghofrani., Eur. Respir. J., 2008, 32, 198-209. [Crossref], [Google Scholar], [Publisher]
    7. Asif., Mini Rev. Med. Chem., 2014, 14, 1093-1103. [Crossref], [Google Scholar], [Publisher]
    8. Asif., Curr. Med. Chem., 2012, 19, 2984-2991. [Crossref], [Google Scholar], [Publisher]
    9. Asif., Central Eur. J. Exp. Biol., 2017, 5, 1-19. [PDF], [Google Scholar], [Publisher]
    10. Gupta, V. Kant, Sci. Int., 2013, 7, 253-260. [Crossref], [Google Scholar], [Publisher]
    11. Yang, N.G. Nickols, B.C. Li, G.K. Marinov, J.W. Said, P.B. Dervan, Proc. Natl. Acad. Sci. U. S. A., 2013, 5, 1863-1868. [Crossref], [Google Scholar], [Publisher]
    12. Almirante, L. Polo, A. Mugnaini, E. rovinciali, P. Rugarli, A. Biancotti, A. Gamba, W. urmann, J. Med. Chem., 1965, 8, 305-312. [Crossref], [Google Scholar], [Publisher]
    13. G. Copping, R.J. Birchmore, K. Wright, D.H. Godson, Pest. Sci., 1984, 15, 280-284. [Crossref], [Google Scholar], [Publisher]
    14. Imran, A. Asif, Russ. J. Bioorg. Chem., 2020, 46, 745-767. [Crossref], [Google Scholar], [Publisher]
    15. Imran, A. Asif, Russ. J. Bioorg. Chem., 2020, 46, 726-744. [Crossref], [Google Scholar], [Publisher]
    16. Asif, M. Imran, Anal. Chem. Lett., 2020, 10, 414-427. [Crossref], [Google Scholar], [Publisher]
    17. T. Alam, M. Asif, Prog. Chem. Biochem. Res., 2020, 3, 81-92. [Crossref], [Google Scholar], [Publisher].
    18. Asif, M.T. Alam, J. Med. Chem. Sci., 2020, 3, 109-117. [Crossref], [Google Scholar], [Publisher].
    19. Deree, J.O. Martins, H. Melbostad, W.H. Loomis, R. Coimbra, Clinics (Sao Paulo), 2008, 63, 321-328. [Crossref], [Google Scholar], [Publisher]
    20. J. Marques, L. Zheng, N. Poulakis, J. Guzman, U. Costabel, Am. J. Respir. Crit. Care Med., 1999, 159, 508-511. [Crossref], [Google Scholar], [Publisher]
    21. Peters-Golden, C. Canetti, P. Mancuso, M.J. Coffey, J. Immunol., 2005, 174, 589-594. [Crossref], [Google Scholar], [Publisher]
    22. Ukena, C. Schudt, G.W. Sybrecht, Biochem. Pharmacol., 1993, 45, 847–851. [Crossref], [Google Scholar], [Publisher]
    23. Shibouta, K. Nishikawa, S. Kikuchi. Arzneimittelforschung, 1978, 28, 1112-1115. [PMID: 226101], [Google Scholar], [Publisher]
    24. P. Kupiecki, J. Lipid Res., 1973, 14, 250-254. [Crossref], [Google Scholar], [Publisher]
    25. G. Baraldi, M.A. Tabrizi, S. Gessi, P.A. Borea, Chem. Rev., 2008, 108, 238–263. [Crossref], [Google Scholar], [Publisher]
    26. P. González, C. Terán, M. Teijeira, Med. Res. Rev., 2008, 28, 329–371. [Crossref], [Google Scholar], [Publisher]
    27. P. de Visser, F.J. Walther, E.H. Laghmani, S. van Wijngaarden, K. Nieuwland, G.T. Wagenaar, Eur. Respir. J., 2008, 31, 633–644. [Crossref], [Google Scholar], [Publisher]
    28. Thota, R. Bansal, Med. Chem. Res., 2010, 19, 808-816. [Crossref], [Google Scholar], [Publisher]
    29. D. Edmondson, A.Mastracchio, J. He, C.C. Chung, M.J. Forrest, S. Hofsess, E. MacIntyre, J. Metzger, N. O'Connor, K. Patel, X. Tong, M.R. Tota, L.H. Van der Ploeg, J.P. Varnerin, M.H. Fisher, M.J. Wyvratt, A.E. Weber, E.R. Parmee, Bioorg. Med. Chem. Lett., 2003, 13, 3983-3987. [Crossref], [Google Scholar], [Publisher]
    30. C. Sellin, A. Alajoutsijärvi, K. Törnquist, M. Fraser, A. Pippuri, I. Ojala, Arzneimittelforschung, 1988, 38, 1787-1789. [PMID: 2854467] [Google Scholar], [Publisher]
    31. Campos-Toimil, I. Estévez, E. Raviña, F. Orallo, Gen. Pharmacol., 1998, 30, 201-207. [Crossref], [Google Scholar], [Publisher]
    32. Mikashima, T. Nakao, K. Goto, H. Ochi, H. Yasuda, T. Tsumagari, Thromb. Res., 1984, 35, 589-594. [Crossref], [Google Scholar], [Publisher]
    33. J. Kanes, J. Tokarczyk, S.J. Siegel, W. Bilker, T. Abel, M.P. Kelly, Neuroscience, 2007, 144, 239-246. [Crossref], [Google Scholar], [Publisher]
    34. R. Maxwell, S.J. Kanes, T. Abel, S.J. Siegel, Neuroscience, 2004, 129, 101–107. [Crossref], [Google Scholar], [Publisher]
    35. C. Yu, J.H. Chen, C.Y. Lai, C.Y., Han, W.C. Ko, Eur J Pharmacol, 2010, 627, 269–75 [Crossref], [Google Scholar], [Publisher]
    36. A.M. Abouzid, N.A. Khalil, E.M. Ahmed, H.A.E. Abd El-Latif, M. El-Araby, Med. Chem. Res., 2010, 19, 629-642. [Crossref], [Google Scholar], [Publisher]
    37. P. Skoumbourdis, C.A.Leclair, E.Stefan, A.G. Turjanski, W.Maguire, S.A. Titus, R. Huang, D.S. Auld, J. Inglese, C.P. Austin, S.W. Michnick, M.Xia, C.J. Thomas,Bioorg. Med. Chem. Lett., 2009, 19, 3686-3692. [Crossref], [Google Scholar], [Publisher]
    38. P. Giovannoni, N. Cesari, A. Graziano, C. Vergelli, C. Biancalani, P. Biagini, V. Dal Piaz. J. Enzyme Inhib. Med. Chem., 2007, 22, 309-218. [Crossref], [Google Scholar], [Publisher]
    39. Pieretti, L. Dominici, A. Di Giannuario, N. Cesari, V. Dal Piaz, Life Sci.,2006, 79, 791-800. [Crossref], [Google Scholar], [Publisher]
    40. Dal Piaz, M.P. Giovannoni, C. Castellana, J.M. Palacios, J. Beleta, T. Doménech, V. Segarra, J. Med. Chem., 1997, 40, 1417-1421. [Crossref], [Google Scholar], [Publisher]
    41. G. Vecsey, G.S. Baillie, D. Jaganath, R. Havekes, A. Daniels, M. Wimmer, T. Huang, K.M. Brown, X.Y. Li, G. Descalzi, S.S. Kim, T. Chen, Y.Z. Shang, M. Zhuo, M.D. Houslay, T. Abel, Nature, 2009, 461, 1122–1125. [Crossref], [Google Scholar], [Publisher]
    42. Dal Piaz, M.C. Castellana, C., Vergelli, M.P. Giovannoni, A. Gavaldà, V. Segarra, J. Beleta, H. Ryder, J.M. Palacios, J. Enzyme Inhib. Med. Chem., 2002, 17, 227-233. [Crossref], [Google Scholar], [Publisher]
    43. Dal Piaz, A. Rascón, M.E. Dubra, M.P. Giovannoni, C. Vergelli, M.C. Castellana. Farmaco, 2002, 57, 89–96. [Crossref], [Google Scholar], [Publisher]
    44. Zhou, P.C. Ting, R. Aslanian, J. Cao, D.W. Kim, R. Kuang, J.F. Lee, J. Schwerdt, H. Wu, R.J. Herr, A.J. Zych, J. Yang, S. Lam, S., Wainhaus, T.A. Black, P.M. McNicholas, Y. Xu, S.S. Walker. Bioorg. Med. Chem. Lett., 2011, 21, 2890–2893. [Crossref], [Google Scholar], [Publisher]
    45. S.R. Murty, B.R. Rao, K.R. Ram, J.S. Yadav, J. Antony, R.J. Anto, Med. Chem. Res., 2012, 21, 3161-3169. [Crossref], [Google Scholar], [Publisher]
    46. Yamada, H. Shimamura, Y. Tsukamoto, A. Yamaguchi, M. Ohki, J. Med. Chem., 1983, 26, 1144-1149. [Crossref], [Google Scholar], [Publisher]
    47. Malinka. Pharmazie, 2001, 56, 384-389. [Crossref], [Google Scholar], [Publisher]
    48. Corsano, G. Strappaghetti, R. Barbaro, G. Giannaccini, L. Betti, A. Lucacchini, Bioorg. Med. Chem., 1999, 7, 933-941. [Crossref], [Google Scholar], [Publisher]
    49. Li, C. Yee, J.A. Beavo. Science, 1999, 283, 848–851. [Crossref], [Google Scholar], [Publisher]
    50. P. Dousa, Kidney Int., 1999, 55, 29–62. [Crossref], [Google Scholar], [Publisher]
    51. Pfister, N. Bennett, F. Bruckert, P. Catty, A. Clerc, F. Pages, P. Deterre, Cell. Signal., 1993, 5, 235–241. [Crossref], [Google Scholar], [Publisher]
    52. L. Jin, F.J. Richard, W.P. Kuo, A.J. D’Ercole, M. Conti, Proc. Natl. Acad. Sci. U.S.A.,1999, 96, 11998-12003. [Crossref], [Google Scholar], [Publisher]
    53. H., Francis, I.V. Turko, J.D. Corbin,Prog. Nucleic Acid Res. Mol. Biol., 2000, 65, 1-52. [Crossref], [Google Scholar], [Publisher]
    54. M. Hetman, N. Robas, R. Baxendale, M. Fidock, S.C. Phillips, S.H. Soderling, J.A. Beavo, Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 12891-12895. [Crossref], [Google Scholar], [Publisher]
    55. D. Houslay, M. Sullivan, G.B. Bolger, Adv. Pharmacol., 1998, 44, 225–342. [Crossref], [Google Scholar], [Publisher]
    56. S. Li, C. Brideau, C.C. Chan, C. Savoie, D. Claveau, S. Charleson, R. Gordon, G. Greig, J.Y. Gauthier, C.K. Lau, D. Riendeau, M. Thérien, E. Wong, P. Prasit, Bioorg. Med. Chem. Lett., 2003, 13, 597–600. [Crossref], [Google Scholar], [Publisher]
    57. Lugnier, Pharmacol. Ther., 2006, 109, 366-398. [Crossref], [Google Scholar], [Publisher]
    58. Cheng, J.P. Grande, Exp. Biol. Med., 2007, 232, 38-51. [Crossref], [Google Scholar], [Publisher]
    59. Haider, G. Heinisch, S. Offenberger, Pharmazie, 1989, 44, 598-601. [Google Scholar], [Publisher]
    60. K. Chintakunta, V. Akella, M.S. Vedula, P.K. Mamnoor, P. Mishra, S.R. Casturi, A. Vangoori, R. Rajagopalan, Eur. J. Med. Chem., 2002, 37, 339–347. [Crossref], [Google Scholar], [Publisher]
    61. Estevez, E. Raviña, E. Sotelo, J. Heterocyclic Chem, 1998, 35, 1421–1428. [Crossref], [Google Scholar], [Publisher]
    62. P. Giovannoni, N. Cesari, A. Graziano, C. Vergelli, C. Biancalani, P. Biagini, V. Dal Piaz, J. Enzyme Inhib. Med. Chem., 2007, 22, 309-318. [Crossref], [Google Scholar], [Publisher]
    63. Okcelik, S. Unlu, E. Banoglu, E. Küpeli, E. Yesilada, M.F. Şahin, Int. J. Pharm. Med. Res., 2003, 336, 406–412. [Crossref], [Google Scholar], [Publisher]
    64. M.C. Toimil, I. Estevez, E. Ravina, F. Orallo, General Pharmacol, 1998, 30, 201-207. [Crossref], [Google Scholar], [Publisher]