title: Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase.
abstract: Human lipoxygenases (LOXs) are a family of iron-containing enzymes which catalyze the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Our group has taken a particular interest in platelet-type 12-(S)-LOX (12-LOX) because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Herein, we report the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. Top compounds, exemplified by 35 and 36, display nM potency against 12-LOX, excellent selectivity over related lipoxygenases and cyclooxygenases, and possess favorable ADME properties. In addition, both compounds inhibit PAR-4 induced aggregation and calcium mobilization in human platelets and reduce 12-HETE in β-cells.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , Rockville, Maryland, United States.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Luci
authors.forename: J Brian
authors.initials: JB
authors.lastname: Jameson
authors.forename: Adam
authors.initials: A
authors.lastname: Yasgar
authors.forename: Giovanni
authors.initials: G
authors.lastname: Diaz
authors.forename: Netra
authors.initials: N
authors.lastname: Joshi
authors.forename: Auric
authors.initials: A
authors.lastname: Kantz
authors.forename: Kate
authors.initials: K
authors.lastname: Markham
authors.forename: Steve
authors.initials: S
authors.lastname: Perry
authors.forename: Norine
authors.initials: N
authors.lastname: Kuhn
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yeung
authors.forename: Edward H
authors.initials: EH
authors.lastname: Kerns
authors.forename: Lena
authors.initials: L
authors.lastname: Schultz
authors.forename: Michael
authors.initials: M
authors.lastname: Holinstat
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.forename: David A
authors.initials: DA
authors.lastname: Taylor-Fishwick
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001555:Benzene Derivatives; D016859:Lipoxygenase Inhibitors; D013449:Sulfonamides; D001092:Arachidonate 12-Lipoxygenase; D002118:Calcium