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
Thomas Jefferson University • Eastern Virginia Medical School • University of California Santa Cruz • US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-10266488-B2
Publication Date
2019-04-23
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 invention relates to potent and selective inhibitors of platelet-type 12-lipoxygenase (12-LOX), specifically 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives. These compounds display nanomolar potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. They demonstrate favorable ADME properties, inhibit platelet aggregation and calcium mobilization induced by protease-activated receptor-4 (PAR4) in human platelets, and reduce 12-HETE levels in mouse and human beta cells. The invention includes pharmaceutical compositions comprising such compounds and methods for using them to treat or prevent 12-LOX mediated diseases or disorders.
The problem solved by the invention addresses the unmet medical need for potent, selective 12-LOX small molecule inhibitors that can be optimized without loss of activity. Prior inhibitors such as ML127 were selectively potent but difficult to optimize due to flat structure-activity relationships, while other known inhibitors lacked the desired potency, selectivity, solubility, and pharmacokinetic properties. Since 12-LOX plays a role in various pathological conditions including skin diseases, diabetes, platelet hemostasis, thrombosis, cancer, and immune-mediated thrombocytopenia such as heparin-induced thrombocytopenia (HIT), a novel class of drug-like inhibitors with good in vitro and in vivo properties was needed.
Claims Coverage
The patent includes five independent claims covering novel compounds and methods for treating thrombosis using these compounds.
Novel 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivative compounds
The compounds have a formula (I) featuring R1 and R2 substituents including H, alkyl, halogen, amine, alkoxy, cycloalkyl, aryl, heterocyclic groups, and R3 selected from various heteroaryl and aryl groups including benzothiazole, benzoxazole, benzimidazole, thiazole, thiophene, quinoline, isoquinoline, pyridine, and others; pharmaceutically acceptable salts and stereoisomers thereof are included.
Specific substitution selections on the R3 group enhancing potency and selectivity
Certain claims specify R3 substituents such as 2-benzothiazole, 4-methyl-2-benzothiazole, 6-methoxy-2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 2-thiophene, 4-phenyl-2-thiazole, 3-quinoline, 8-isoquinoline, various phenyl and naphthalene derivatives, 4N-boc-piperidine-3-phenyl, and 3-isopropyl-phenyl as preferred for improved activity.
Methods for treating or preventing thrombosis using the compounds
Administration of a therapeutically or prophylactically effective amount of the compounds or their salts to a mammal for treatment or prevention of thrombosis, highlighting the therapeutic use of these selective 12-LOX inhibitors.
The claimed invention covers novel substituted benzenesulfonamide compounds with high selectivity and potency against 12-LOX, particular preferred substitutions enhancing activity, and therapeutic methods using these compounds to treat or prevent thrombosis.
Stated Advantages
Potent and selective inhibition of 12-LOX with nanomolar potency and excellent selectivity over related lipoxygenases and cyclooxygenases.
Favorable ADME properties including good microsomal stability, plasma stability, solubility, and moderate oral bioavailability with beneficial in vivo pharmacokinetics.
Capability to inhibit PAR4 induced platelet aggregation and calcium mobilization, reducing 12-HETE production in relevant cell types, highlighting therapeutic potential in platelet-related diseases.
The compounds exemplify a novel chemotype distinct from previously known inhibitors, with improved structure-activity relationships and amenability to chemical modification for optimization.
Potential to treat or prevent immune-mediated thrombocytopenia and thrombosis disorders such as heparin-induced thrombocytopenia (HIT), mitigating serious thrombotic events with a mechanism distinct from existing therapies.
Documented Applications
Treatment or prevention of 12-lipoxygenase mediated diseases and disorders including skin diseases, diabetes type 1 and 2, diabetic kidney and nerve diseases, cardiovascular diseases, congestive heart failure, myocardial infarction, stroke, Alzheimer's disease, non-alcoholic steatohepatitis, platelet hemostasis, heparin-induced thrombocytopenia, thrombosis, and cancers such as prostate, colorectal, breast, and lung cancer.
Use in methods for inhibiting platelet activation, including immune-mediated platelet activation resulting from FcγRIIa receptor activation.
Use in transplantation/xenotransplantation scenarios to improve survival of islet transplants by ex vivo treatment.
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