PT  - JOURNAL ARTICLE
AU  - Carlo Pergola
AU  - Bianca Jazzar
AU  - Antonietta Rossi
AU  - Ulrike Buehring
AU  - Susann Luderer
AU  - Friederike Dehm
AU  - Hinnak Northoff
AU  - Lidia Sautebin
AU  - Oliver Werz
TI  - Cinnamyl-3,4-Dihydroxy-α-Cyanocinnamate Is a Potent Inhibitor of 5-Lipoxygenase
AID  - 10.1124/jpet.111.180794
DP  - 2011 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 205--213
VI  - 338
IP  - 1
4099  - http://jpet.aspetjournals.org/content/338/1/205.short
4100  - http://jpet.aspetjournals.org/content/338/1/205.full
SO  - J Pharmacol Exp Ther2011 Jul 01; 338
AB  - Lipoxygenases (LOs) are iron-containing enzymes that catalyze the conversion of arachidonic acid into hydroperoxyeicosatetraenoic acids (HPETEs) and other bioactive lipid mediators. In mammals, 5-LO, 15-LO, and 12-LO enzymes seem to have distinct roles in pathophysiological contexts, which have emphasized the need for selective inhibitors. Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) has been proposed as potent and selective inhibitor of platelet-type 12-LO (p12-LO). Here, we re-evaluated the selectivity profile of CDC on LOs, and we show that CDC is a potent and direct inhibitor of 5-LO. CDC reduced 5-LO activity in cell-free assays (purified human recombinant enzyme or leukocyte homogenates), with IC50 values in the low nanomolar range (9–25 nM) and a selectivity index of approximately 35 and 15 over p12-LO and 15-LO1, respectively. Likewise, CDC inhibited 5-LO product formation in intact human polymorphonuclear leukocytes and monocytes (IC50 = 0.45–0.8 μM). A lower potency was observed for 15-LO1, whereas p12-LO activity in platelets was hardly affected. In human whole blood, CDC efficiently reduced the formation of 5-LO products, and similar effects were observed for 12(S)-H(P)ETE and 15(S)-H(P)ETE. Finally, CDC (3.5 and 7 mg/kg i.p.) was effective in vivo in the platelet-activating factor-induced shock in mice and reduced formation of the 5-LO product leukotriene B4 in the rat carrageenan-induced pleurisy after a single oral dose of 10 mg/kg. Together, our data demonstrate that CDC is a potent inhibitor of 5-LO with efficacy in vivo and encourage further development of CDC as the lead compound.