title: Isomeric acetoxy analogs of celecoxib and their evaluation as cyclooxygenase inhibitors.
abstract: A group of celecoxib analogs having a SO(2)NH(2) (9a-f), or SO(2)Me (12a-f), COX-2 pharmacophore at the para-position of the N-1 phenyl ring in conjunction with a C-5 phenyl ring having a variety of substituents (4-, 3-, 2-OAc; 4-Me,2-OAc, 4-Me,3-OAc, 4-F,2-OAc) was synthesized for evaluation as cyclooxygenase (COX) inhibitors of the COX-1/COX-2 isozymes. Within this group of compounds, 1-(4-aminosulfonylphenyl)-3-trifluoromethyl-5-(2-acetoxy-4-fluorophenyl)pyrazole (9f) emerged as the most potent (COX-1 IC(50)=0.7 μM; COX-2 IC(50)=0.015 μM) and selective (COX-2 selectivity index=47) inhibitor agent that exhibited good anti-inflammatory activity (ED(50)=42.3mg/kg) which was lower than the reference drug celecoxib (ED(50)=10.8 mg/kg), but greater than ibuprofen (ED(50)=67.4 mg/kg) and aspirin (ED(50)=128.7 mg/kg). Molecular modeling studies for 9f showed that the SO(2)NH(2) group assumes a position within the secondary pocket of the COX-2 active site wherein the SO(2)NH(2) oxygen atom is hydrogen bonded to the H90 residue (2.90Å), the SO(2)NH(2) nitrogen atom forms a hydrogen bond with L352 (N⋯O=2.80Å), and the acetyl group is positioned in the vicinity of the S530 residue where the acetyl oxygen atom undergoes hydrogen bonding to L531 (2.99Å).
authors: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
authors: M
authors: M
authors: Abdur Rahim
authors: P N
authors: PN
authors: Praveen Rao
authors: Atul
authors: A
authors: Bhardwaj
authors: Jatinder
authors: J
authors: Kaur
authors: Zhangjian
authors: Z
authors: Huang
authors: Edward E
authors: EE
authors: Knaus
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib