Synthesis, Anti‐Inflammatory Activity, and COX‐1/2 Inhibition Profile of Some Novel Non‐Acidic Polysubstituted Pyrazoles and Pyrano[2,3‐c]pyrazoles

The synthesis and evaluation of the anti‐inflammatory activity of some structure hybrids comprising basically the 5‐hydroxy‐3‐methyl‐1‐phenyl‐4‐substituted‐1H‐pyrazole scaffold directly linked to a variety of heterocycles and functionalities, or annulated as pyrano[2,3‐c]pyrazoles, is described. Acc...

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Veröffentlicht in:Archiv der Pharmazie (Weinheim) 2017-05, Vol.350 (5), p.n/a
Hauptverfasser: Faidallah, Hassan M., Rostom, Sherif A. F.
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Sprache:eng
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Zusammenfassung:The synthesis and evaluation of the anti‐inflammatory activity of some structure hybrids comprising basically the 5‐hydroxy‐3‐methyl‐1‐phenyl‐4‐substituted‐1H‐pyrazole scaffold directly linked to a variety of heterocycles and functionalities, or annulated as pyrano[2,3‐c]pyrazoles, is described. According to the in vivo results and a comprehensive structure–activity relationship study, five analogs (5, 10, 17, 19, and 27) displayed remarkable anti‐inflammatory profiles showing distinctive % protection and ED50 values, especially 10 and 27 (ED50 35.7 and 38.7 μmol/kg, respectively) which were nearly equiactive to celecoxib (ED50 32.1 μmol/kg). Compounds 10, 17, and 27 exhibited distinctive COX‐2 inhibition with a noticeable COX‐2 selectivity (SI values 7.83, 6.87, and 7.16, respectively), close to that of celecoxib (SI 8.68). Additionally, 5, 10, 17, 19, and 27 proved to be gastrointestinal tract safe (0–20% ulceration) and non‐toxic, being well tolerated by the experimental animals up to 250 mg/kg orally and 80 mg/kg parenterally. Collectively, the in vivo ED50 values for the most potent five derivatives agree with their in vitro COX‐2 selectivity indices, suggesting their usefulness as selective anti‐inflammatory COX‐2 inhibitors. The bipyrazole 10 and the pyranopyrazole 27 could be considered as the most active members in this study, being nearly equiactive to celecoxib, besides their obvious selective COX‐2 inhibition, high safety margin, and predicted pharmacokinetic (ADME‐T) suitability for oral use. Novel polysubstituted pyrazoles and pyranopyrazoles were synthesized and evaluated for their in vivo and in vitro anti‐inflammatory activities. Five analogs (5, 10, 17, 19, and 27) displayed in vivo ED50 values that correspond to the in vitro COX‐2 selectivity indices. Bipyrazole 10 and pyranopyrazole 27 (structurally related to celecoxib) showed the highest anti‐inflammatory and COX‐2 inhibitory activities with GIT‐sparing profiles and high safety margins.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.201700025