Τόμος 34 (2020) – Τεύχος 1 –Άρθρο 2 – Review of Clinical Pharmacology and Pharmacokinetics – Διεθνής Έκδοση – Volume 34 (2020) – Issue 1 – Article 2 – Review of Clinical Pharmacology and Pharmacokinetics – International Edition

Aggeliki Roumana, Aikaterini I. Argyriou, Garyfallia I. Makrynitsa, Styliani Chasapi, Minos-Timotheos Matsoukas, Stavros Topouzis

Laboratory of Medicinal Chemistry, Department of Pharmacy, School of Health Sciences, University of Patras, Patras GR-26504, Greece

Group of Biomolecular Simulations & NMR, Department of Pharmacy, School of Health Sciences, University of Patras, Patras GR-26504, Greece

Laboratory of Molecular Pharmacology, Department of Pharmacy, School of Health Sciences, University of Patras, Patras GR-26504, Greece

The heme enzyme soluble Guanylate Cyclase (sGC) is a pivotal amplification target in the NO-sGC-cGMP pathway, converting guanosine-5΄-triphoshate (GTP) to cyclic guanosine-3΄,5΄-monophosphate (cGMP) in response to its major physiological stimulant, nitric oxide (NO). However, several pathologies are etiologically linked with loss of the heme moiety by sGC, resulting in unresponsiveness to NO and ensuing dysfunction of the whole axis. We report the synthesis of HMR-1766 (Ataciguat), a heme-independent sGC “activator” which binds in the heme pocket of sGC, following a modified approach described in the original patent and the ability of our product to increase cGMP levels in the cancer cell line LNCaP, following oxidation of the sGC heme. Furthermore, we describe a docking virtual screening-based strategy, which enables the identification of novel, similar-acting compounds as putative therapeutic molecules.

1. Tsai, E.J. and D.A. Kass, Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacology & therapeutics, 2009. 122(3): p. 216-238.
2. Papapetropoulos, A., A.J. Hobbs, and S. Topouzis, Extending the translational potential of targeting NO/cGMP‐regulated pathways in the CVS. British journal of pharmacology, 2015. 172(6): p. 1397-1414.
3. Vanhoutte, P.M., et al., Thirty years of saying NO: sources, fate, actions, and misfortunes of the endothelium-derived vasodilator mediator.Circulation research, 2016. 119(2): p. 375-396.
4. Hollas, M.A., et al., Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery. Nitric Oxide, 2019. 82: p. 59-74.
5. Ignarro, L.J., Nitric oxide is not just blowing in the wind. British journal of pharmacology, 2019. 176(2): p. 131-134.
6. Keravis, T. and C. Lugnier, Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. British journal of pharmacology, 2012. 165(5): p. 1288-1305.
7. Andersson, K.E., PDE5 inhibitors–pharmacology and clinical applications 20 years after sildenafil discovery. British journal of pharmacology, 2018. 175(13): p. 2554-2565.
8. Follmann, M., et al., The chemistry and biology of soluble guanylate cyclase stimulators and activators. Angewandte Chemie International Edition, 2013. 52(36): p. 9442-9462.
9. Sandner, P., et al., Soluble Guanylate Cyclase Stimulators and Activators. Handbook of experimental pharmacology, 2018, Springer. p. 1-40.
10. Breitenstein, S., et al., Novel sGC stimulators and sGC activators for the treatment of heart failure, in Heart Failure. 2016, Springer. p. 225-247.
11. Buys, E., et al., Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. Nitric Oxide, 2018. 78: p. 72-80.
12. Stasch, J.-P. and O.V. Evgenov, Soluble guanylate cyclase stimulators in pulmonary hypertension, in Pharmacotherapy of Pulmonary Hypertension. 2013, Springer. p. 279-313.
13. Ghofrani, H.-A., et al., Riociguat: mode of action and clinical development in pulmonary hypertension. Chest, 2017. 151(2): p. 468-480.
14. Lian, T.-Y., X. Jiang, and Z.-C. Jing, Riociguat: a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. Drug design, development and therapy, 2017. 11: p. 1195.
15. Schindler, U., et al., Biochemistry and pharmacology of novel anthranilic acid derivatives activating heme-oxidized soluble guanylyl cyclase.Molecular pharmacology, 2006. 69(4): p. 1260-1268.
16. Zhou, Z., et al., Soluble guanylyl cyclase activation by HMR-1766 (ataciguat) in cells exposed to oxidative stress. American Journal of Physiology-Heart and Circulatory Physiology, 2008. 295(4): p. H1763-H1771.
17. Schäfer, A., et al., Guanylyl cyclase activator ataciguat improves vascular function and reduces platelet activation in heart failure. Pharmacological research, 2010. 62(5): p. 432-438.
18. Sömmer, A., P. Sandner, and S. Behrends, BAY 60–2770 activates two isoforms of nitric oxide sensitive guanylyl cyclase: Evidence for stable insertion of activator drugs. Biochemical pharmacology, 2018. 147: p. 10-20.
19. Haramis, G., et al., cGMP‐independent anti‐tumour actions of the inhibitor of soluble guanylyl cyclase, ODQ, in prostate cancer cell lines. British journal of pharmacology, 2008. 155(6): p. 804-813.
20. Kumar, V., et al., Insights into BAY 60-2770 activation and S-nitrosylation-dependent desensitization of soluble guanylyl cyclase via crystal structures of homologous nostoc H-NOX domain complexes. Biochemistry, 2013. 52(20): p. 3601-3608.
21. Sterling, T. and J.J. Irwin, ZINC 15–ligand discovery for everyone. Journal of chemical information and modeling, 2015. 55(11): p. 2324-2337.
22. Makrynitsa, G.I., et al., Therapeutic Targeting of the Soluble Guanylate Cyclase. Current medicinal chemistry, 2019.
23. Trott, O. and A.J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry, 2010. 31(2): p. 455-461.
24. Gütlein, M., A. Karwath, and S. Kramer, CheS-Mapper 2.0 for visual validation of (Q) SAR models. Journal of cheminformatics, 2014. 6(1): p. 41.
25. Yadav, M.R., R.K. Rit, and A.K. Sahoo, Sulfoximine Directed Intermolecular o-C–H Amidation of Arenes with Sulfonyl Azides. Organic letters, 2013. 15(7): p. 1638-1641.
26. Hunt, C.A., et al., 3-Substituted thieno [2, 3-b][1, 4] thiazine-6-sulfonamides. A novel class of topically active carbonic anhydrase inhibitors. Journal of medicinal chemistry, 1994. 37(2): p. 240-247.
27. Schindler U., Schönafinger K., Strobel H.: Sulfur substituted sulfonylaminocarboxylic acid N-arylamides, their preparation, their use and pharmaceutical preparations comprising them. WO0002581