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

Abstract

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 IC50 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 IC50 values and showed no discernable toxicity after repeated dosing. These results reveal a novel strategy to inhibit PDE5 with unprecedented potency and isozyme selectivity.

Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells

“…The synthetic routes of the thiazolyl–pyrazoline derivatives 3a – c , 6a – l and 9a – f are considered in Chart 1 , Chart 2 and Chart 3 . First, the 3-(4-aryl)-1-(3,4-dimethoxyphenyl)prop-2-en-1-ones 2a – c were obtained through the Claisen–Schmidt reaction [ 53 ] by direct condensation of aromatic aldehydes 1a–c with dimethoxy acetophenone in the presence of sodium hydroxide [ 54 , 55 , 56 ]. This step was followed by the reaction of compounds 2a – c with thiosemicarbazide under a basic condition to give 3-(3,4-dimethoxyphenyl)-5-(4-aryl)-4,5-dihydro-1 H -pyrazole-1-carbothioamides 3a – c , respectively ( Chart 1 ) [ 57 , 58 ].…”

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum maxim. as PDE5A inhibitors

“…The development of PDE5 inhibitor, an important drug target for ED, has attracted much attention in the field. The common assays for screening PDE5 inhibitors use labeled cGMP as substrate, among which, 3 [H] is the main isobaric tags [ 21 – 23 ]. Other detection methods using fluorescence detection, such as fluorescence resonance energy transfer (FRET) [ 24 ] and fluorescence polarization (FP) [ 25 ], are also used occasionally.…”

Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of Chalcones in Water: Application to the Enantioselective Synthesis of Flavans BW683C and Tephrowatsin E

“…13 C { 1 H} NMR (101 MHz, CDCl 3 , Me 4 Si) δ 193.3, 161.6, 158.0, 143.5, 132.7, 130.3, 130.2, 129.6, 127.9, 125.0, 120.8, 114.4, 111.7, 55.8, 55.5. Spectroscopic data were consistent with those reported in the literature …”

“…Spectroscopic data were consistent with those reported in the literature. 34 (E)-1-(3,5-Dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1one (1f). From 5 mmol of 3′,5′-dimethoxyacetophenone and 5 mmol of 4-anisaldehyde.…”