Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors

• Published in: Bioorganic chemistry 2020-11, Vol.104, p.104322-104322, Article 104322
• Main Authors: Abdel-Halim, Mohammad, Tinsley, Heather, Keeton, Adam B., Weam, Mohammed, Atta, Noha H., Hammam, Mennatallah A., Hefnawy, Amr, Hartmann, Rolf W., Engel, Matthias, Piazza, Gary A., Abadi, Ashraf H.
• Format: Article
• Language: English
• Subjects: Celecoxib; cGMP elevation; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; PDE5; PDE5 inhibitors; Phosphodiesterase 5 Inhibitors - chemical synthesis; Phosphodiesterase 5 Inhibitors - chemistry; Phosphodiesterase 5 Inhibitors - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazoline; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104322

[Display omitted] •A novel class of trisubstituted pyrazolines as PDE5 inhibitors was discovered.•The compounds were developed inspired by the off-target activity of celecoxib against PDE5.•The developed compounds showed promising selectivity profile.•The developed compounds could increase intracellular cGMP levels in HEK293 cells. Celecoxib, is a selective cyclooxygenase-2 (COX2) inhibitor with a 1,5-diaryl pyrazole scaffold. Celecoxib has a better safety profile compared to other COX2 inhibitors having side effects of systemic hypertension and thromboembolic complications. This may be partly attributed to an off-target activity involving phosphodiesterase 5 (PDE5) inhibition and the potentiation of NO/cGMP signalling allowing coronary vasodilation and aortic relaxation. Inspired by the structure of celecoxib, we synthesized a chemically diverse series of compounds containing a 1,3,5-trisubstituted pyrazoline scaffold to improve PDE5 inhibitory potency, while eliminating COX2 inhibitory activity. SAR studies for PDE5 inhibition revealed an essential role for a carboxylic acid functionality at the 1-phenyl and the importance of the non-planar pyrazoline core over the planar pyrazole with the 5-phenyl moiety tolerating a range of substituents. These modifications led to new PDE5 inhibitors with approximately 20-fold improved potency to inhibit PDE5 and no COX-2 inhibitory activity compared with celecoxib. PDE isozyme profiling of compound 11 revealed a favorable selectivity profile. These results suggest that trisubstituted pyrazolines provide a promising scaffold for further chemical optimization to identify novel PDE5 inhibitors with potential for less side effects compared with available PDE5 inhibitors used for the treatment of penile erectile dysfunction and pulmonary hypertension.