Trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic acid: a new lead compound with selective COX-2 inhibitory activity.
A novel series of 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic acid derivatives was designed and synthesized by a new one-step pathway. Structure elucidation of the synthesized compounds was confirmed by various spectral and elemental analyses. The prepared compounds were evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes in vitro. Among the synthesized compounds, the 2-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)acetic acid 4 emerged as the most potent COX-2 inhibitor (IC(50)  value: 150 nM) with the highest selectivity index (COX-1/COX-2 inhibition ratio: 570.6). Docking studies of compound 4 in the active site of COX-2 recognized its potential binding mode to the enzyme. Based on the preliminary results, compound 4 was considered as a lead compound for further optimization.
Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt. hamdym01@yahoo.com
Hamdy M
HM
Abdel-Rahman
Keriman
K
Ozadali
D000818:Animals; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D012756:Sheep; D013329:Structure-Activity Relationship
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007191:Indazoles; D051545:Cyclooxygenase 1