(Carboxyalkyl)benzyl propargyl ethers as selective inhibitors of leukocyte-type 12-lipoxygenases

Journal of Medicinal Chemistry
G GorinsL J Marnett

Abstract

A series of (carboxyalkyl)benzyl propargyl ethers was synthesized and tested as inhibitors of 12-lipoxygenase (12-LO) from porcine leukocyte cytosol. Optimum activity was displayed by 3-[4-[(2-tridecynyloxy)methyl]phenyl]propanoic acid. Altering the length of the alkyl side chain attached to the acetylenic group reduced activity. Changing the substitution pattern in the (carboxyalkyl)benzyl group from para to meta or ortho also reduced activity. Analogs in which the triple bond was replaced by a double bond or an allene displayed reduced activity, whereas fully saturated analogs were inactive. High concentrations (10 microM) of the most potent acetylenic (carboxylalkyl)benzyl ethers did not inhibit human platelet 12-LO, human neutrophil 5-LO, rabbit reticulocyte 15-LO, or soybean 15-LO. Thus, this class of compounds represents the first example of isoform specific LO inhibitors.

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Citations

Dec 2, 2004·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Masayoshi Abe, Tanihiro Yoshimoto
Sep 7, 2000·Biochemical and Biophysical Research Communications·H SuzukiT Suzuki
Sep 21, 2005·Biochemical and Biophysical Research Communications·Shozo YamamotoNatsuo Ueda
Oct 24, 2014·Accounts of Chemical Research·Betty J Gaffney
May 31, 2018·Journal of Receptor and Signal Transduction Research·Sharanya C SHaridas M
Jun 7, 2006·Chembiochem : a European Journal of Chemical Biology·Stephan HerreHartmut Kuhn
Feb 6, 2010·Organic & Biomolecular Chemistry·Ya-Jun Jian, Yikang Wu
Feb 18, 2015·Chembiochem : a European Journal of Chemical Biology·Dries J H De ClercqSerge Van Calenbergh
Feb 17, 2006·Journal of Medicinal Chemistry·Victor KenyonMatthew P Jacobson

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