Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases.
A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO2Me COX-2 pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities. Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50 = 0.1 microM; SI = 300), being 5-fold more potent than rofecoxib (COX-2 IC50 = 0.5 microM; SI > 200). In a rat carrageenan-induced paw edema assay 13h exhibited moderate antiinflammatory activity (26% inhibition of inflammation) at 3 h after administration of a 30 mg/kg oral dose. A related dual COX-1/2 and 5/15-LOX inhibitor 3-(4-methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g, COX-1 IC50 = 31.5 microM; COX-2 IC50 = 1.0 microM; SI = 31.5; 5-LOX IC50 = 1.0 microM; 15-LOX IC50 = 3.2 microM) exhibited more potent antiinflammatory activity (ED50 = 90 mg/kg), being superior to the reference drug aspirin (ED50 = 129 mg/kg). Within this group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC50 = 9.2 microM; COX-2 IC50 = 0.32 microM; SI = 28; 5-LOX IC50 = 0.32 microM; 15-LOX IC50 = 0.36 microM) in conjunction with a good antiinflammatory activity (ED50 = 35 mg/kg) compared to the reference drug celecoxib (ED50 = 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2 binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344, Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3 p-SO2Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513, Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3 p-SO2Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.
Rao
P N Praveen
PN
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8, Canada.
Chen
Qiao-Hong
QH
Knaus
Edward E
EE
D000284:Administration, Oral; D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D010147:Pain Measurement; D051381:Rats; D013329:Structure-Activity Relationship
D000480:Alkynes; D000700:Analgesics; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; C022030:methylacetylene; D002351:Carrageenan; D001093:Arachidonate 15-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2