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Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases.
J Med Chem. 2006 Mar 09; 49(5):1668-83.JM

Abstract

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.

Authors+Show Affiliations

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8, Canada.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16509583

Citation

Rao, P N Praveen, et al. "Synthesis and Structure-activity Relationship Studies of 1,3-diarylprop-2-yn-1-ones: Dual Inhibitors of Cyclooxygenases and Lipoxygenases." Journal of Medicinal Chemistry, vol. 49, no. 5, 2006, pp. 1668-83.
Rao PN, Chen QH, Knaus EE. Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases. J Med Chem. 2006;49(5):1668-83.
Rao, P. N., Chen, Q. H., & Knaus, E. E. (2006). Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases. Journal of Medicinal Chemistry, 49(5), 1668-83.
Rao PN, Chen QH, Knaus EE. Synthesis and Structure-activity Relationship Studies of 1,3-diarylprop-2-yn-1-ones: Dual Inhibitors of Cyclooxygenases and Lipoxygenases. J Med Chem. 2006 Mar 9;49(5):1668-83. PubMed PMID: 16509583.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases. AU - Rao,P N Praveen, AU - Chen,Qiao-Hong, AU - Knaus,Edward E, PY - 2006/3/3/pubmed PY - 2006/4/28/medline PY - 2006/3/3/entrez SP - 1668 EP - 83 JF - Journal of medicinal chemistry JO - J Med Chem VL - 49 IS - 5 N2 - 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. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/16509583/Synthesis_and_structure_activity_relationship_studies_of_13_diarylprop_2_yn_1_ones:_dual_inhibitors_of_cyclooxygenases_and_lipoxygenases_ L2 - https://doi.org/10.1021/jm0510474 DB - PRIME DP - Unbound Medicine ER -