From Celecoxib to a Novel Class of Phosphodiesterase 5 Inhibitors: Trisubstituted Pyrazolines as Novel Phosphodiesterase 5 Inhibitors with Extremely High Potency and Phosphodiesterase Isozyme Selectivity.

Autor: Abdel-Halim M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt., Sigler S; Departments of Oncologic Sciences and Pharmacology, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, Alabama 36604, United States., Racheed NAS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt., Hefnawy A; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt., Fathalla RK; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.; Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany., Hammam MA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt., Maher A; Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 11266, Egypt., Maxuitenko Y; Departments of Oncologic Sciences and Pharmacology, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, Alabama 36604, United States., Keeton AB; Departments of Oncologic Sciences and Pharmacology, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, Alabama 36604, United States., Hartmann RW; Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany., Engel M; Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany., Piazza GA; Departments of Oncologic Sciences and Pharmacology, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, Alabama 36604, United States., Abadi AH; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2021 Apr 22; Vol. 64 (8), pp. 4462-4477. Date of Electronic Publication: 2021 Apr 01.
DOI: 10.1021/acs.jmedchem.0c01120
Abstrakt: A ligand-based approach involving systematic modifications of a trisubstituted pyrazoline scaffold derived from the COX2 inhibitor, celecoxib, was used to develop novel PDE5 inhibitors. Novel pyrazolines were identified with potent PDE5 inhibitory activity lacking COX2 inhibitory activity. Compound d12 was the most potent with an IC 50 of 1 nM, which was three times more potent than sildenafil and more selective with a selectivity index of >10,000-fold against all other PDE isozymes. Sildenafil inhibited the full-length and catalytic fragment of PDE5, while compound d12 only inhibited the full-length enzyme, suggesting a mechanism of enzyme inhibition distinct from sildenafil. The PDE5 inhibitory activity of compound d12 was confirmed in cells using a cGMP biosensor assay. Oral administration of compound d12 achieved plasma levels >1000-fold higher than IC 50 values and showed no discernable toxicity after repeated dosing. These results reveal a novel strategy to inhibit PDE5 with unprecedented potency and isozyme selectivity.
Databáze: MEDLINE
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