Design and synthesis of acyclic triaryl ( Z)-olefins: a novel class of cyclooxygenase-2 (COX-2) inhibitors

Abstract

A group of acyclic 2-alkyl-1,1-diphenyl-2-(4-methylsulfonylphenyl)ethenes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure–activity studies identified 1,1-diphenyl-2-(4-methylsulfonylphenyl)hex-1-ene as a highly potent (IC 50 = 0.014 μM), and an extremely selective [COX-2 selectivity index (SI) > 7142], COX-2 inhibitor that showed superior anti-inflammatory (AI) activity (ID 50 = 2.5 mg/kg) relative to celecoxib (ID 50 = 10.8 mg/kg). This initial study was extended to include the design of a structurally related group of acyclic triaryl ( Z)-olefins possessing an acetoxy (OAc) substituent at the para-position of the C-1 phenyl ring that is cis to a C-2 4-methylsulfonylphenyl substituent. COX-1 and COX-2 inhibition studies showed that ( Z)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene [( Z)- 13b] is a potent (COX-1 IC 50 = 2.4 μM; COX-2 IC 50 = 0.03 μM), and selective (COX-2 SI = 81), COX-2 inhibitor which is a potent AI agent (ID 50 = 4.1 mg/kg) with equipotent analgesic activity to celecoxib. A molecular modeling (docking) study showed that the SO 2Me substituent of ( Z)- 13b inserts deep inside the 2°-pocket of the COX-2 active site, where one of the O-atoms of S O 2 group undergoes a H-bonding interaction with Phe 518. The p-OAc substituent on the C-1 phenyl ring is oriented in a hydrophobic pocket comprised of Met 522, Gly 526, Trp 387, Tyr 348, and Tyr 385, and the C-2 ethyl substituent is oriented towards the mouth of the COX-2 channel in the vicinity of amino acid residues Arg 120, Leu 531, and Val 349. Structure–activity data acquired indicate that a ( Z)-olefin having cis C-1 4-acetoxyphenyl (phenyl) and C-2 4-methylsulfonylphenyl substituents, and a C-1 phenyl substituent in conjunction with either a C-2 hydrogen or short alkyl substituent provides a novel template to design acyclic olefinic COX-2 inhibitors that, like aspirin, have the potential to acetylate COX-2.