4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
Inventors
Maloney, David J. • Luci, Diane K. • Jadhav, Ajit • Holman, Theodore • Nadler, Jerry L. • Holinstat, Michael • Taylor-Fishwick, David • Simeonov, Anton • YASGAR, Adam • McKenzie, Steven
Assignees
United States, Department Of Health • Thomas Jefferson University • Eastern Virginia Medical School • University of California Santa Barbara UCSB • University of California Santa Cruz • Office of Technology Transfer
Publication Number
US-10752581-B2
Publication Date
2020-08-25
Expiration Date
2034-10-10
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Abstract
Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing 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. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.
Core Innovation
The present invention discloses a novel class of compounds based on the 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide scaffold that are potent and selective inhibitors of platelet-type 12-lipoxygenase (12-LOX). These compounds exhibit nanomolar potency against 12-LOX with excellent selectivity over related lipoxygenases such as 5-LOX, 15-LOX-1, 15-LOX-2, and over cyclooxygenases COX-1 and COX-2. The compounds have favorable absorption, distribution, metabolism, and excretion (ADME) properties, good in vivo pharmacokinetics, and successfully inhibit platelet aggregation and calcium mobilization induced by PAR-4 activation in human platelets. Furthermore, they reduce 12-HETE production in mouse and human beta cells, suggesting utility in diabetes-related applications. Methods of synthesizing these compounds and pharmaceutical compositions comprising them are also disclosed, along with methods for treating or preventing diseases mediated by 12-lipoxygenase using these inhibitors.
The problem addressed arises from the lack of potent, selective, and readily optimizable small molecule inhibitors of 12-lipoxygenase. Existing inhibitors such as ML127 displayed potent and selective activity but had flat structure-activity relationships (SAR) limiting further optimization, and other known inhibitors lacked potency or selectivity. There is a need for new 12-LOX inhibitors that possess high potency, selectivity, favorable solubility, and pharmacokinetic profiles enabling therapeutic use in 12-LOX mediated diseases such as diabetes, cancer, thrombosis, skin diseases, neurodegenerative diseases, and cardiovascular disorders.
Claims Coverage
The patent contains multiple independent claims defining distinct inventive features focused on chemical compounds of specified formulas and their therapeutic uses.
Chemical compounds of formula variants
Compounds characterized by Formula (I) and additional formulas (II) through (VII), where substituents R1, R2, and R3 are selected from defined groups including alkyl, halogen, aryl, heteroaryl, and others, optionally substituted with various groups, and including pharmaceutically acceptable salts, enantiomers, and diastereomers.
Selective substitution patterns of R1, R2, and R3
Substitutions where R1 is methoxy or Cl when R2 is hydrogen, and R2 is Br or Cl when R1 is hydrogen, with R3 selected from specific heterocycles and substituted aryl groups, defining a set of preferred compounds.
Pharmaceutical compositions including the compounds
Compositions comprising the compounds of formulae (I)-(VII), salts, enantiomers, mixtures thereof, and pharmaceutically acceptable carriers.
Methods of treating or preventing 12-lipoxygenase mediated diseases
Use of the disclosed compounds and their salts or isomers in treating or preventing diseases or disorders mediated by 12-lipoxygenase by administering therapeutically or prophylactically effective amounts to mammals.
The claims cover novel chemical entities with defined substituents, pharmaceutical compositions containing these entities, and therapeutic methods employing these compounds to inhibit 12-lipoxygenase mediated diseases, establishing the invention's chemical, compositional, and therapeutic scope.
Stated Advantages
Potent nanomolar inhibition of 12-lipoxygenase with excellent selectivity over related lipoxygenases and cyclooxygenases.
Favorable ADME properties and good in vivo pharmacokinetics including microsomal and plasma stability and oral bioavailability.
Ability to inhibit platelet aggregation and calcium mobilization induced by PAR-4 receptor activation, relevant to thrombosis.
Inhibition of 12-HETE production in beta cells, indicating potential utility in diabetes treatment.
Structural scaffold amenable to structural modification, enabling systematic SAR studies and optimization.
Documented Applications
Treatment or prevention of 12-lipoxygenase mediated diseases such as type 1 and type 2 diabetes, diabetic kidney and nerve disease.
Treatment or prevention of cardiovascular diseases including congestive heart failure, myocardial infarction, and stroke.
Treatment or prevention of thrombosis and heparin-induced thrombocytopenia.
Treatment or prevention of cancers including prostate, colorectal, breast, and lung cancers.
Treatment of Alzheimer's disease, skin diseases, and non-alcoholic steatohepatitis.
Use in transplantation scenarios to improve islet survival prior to transplant.
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