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 • US Department of Health and Human Services
Publication Number
US-11274077-B2
Publication Date
2022-03-15
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
Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to produce bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are implicated in physiological processes including platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) plays a significant role in various diseases such as skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. The invention discloses 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives that are potent and selective inhibitors of 12-LOX, exhibiting nanomolar potency and excellent selectivity over other lipoxygenases and cyclooxygenases.
The invention addresses the lack of potent, selective 12-LOX small molecule inhibitors that can be optimized without losing activity. Prior inhibitors like ML127 showed excellent selectivity but were difficult to optimize, and earlier inhibitors were less potent and less selective. The disclosed compounds possess favorable absorption, distribution, metabolism, and excretion (ADME) properties, good pharmacokinetic (PK) profiles, and demonstrated activity in relevant biological models by inhibiting platelet aggregation, calcium mobilization, and 12-HETE production in beta cells and human islets.
Furthermore, the invention reveals the essential role of platelet 12-LOX in FcγRIIa-mediated platelet activation, a pathway involved in immune-mediated thrombocytopenia and thrombosis such as heparin-induced thrombocytopenia (HIT). By inhibiting 12-LOX, the compounds reduce platelet activation, thereby potentially limiting thrombotic complications. The invention also provides compositions and methods for treating or preventing 12-LOX mediated diseases including different forms of diabetes, cardiovascular diseases, thrombosis, skin diseases, neurodegenerative diseases, and various cancers.
Claims Coverage
The patent includes multiple independent claims primarily directed to methods of treating 12-lipoxygenase mediated diseases by administering specified compounds, and the compounds defined by various chemical formulae. The inventive features focus on chemical structures, substitutions, and therapeutic applications in disease treatment.
Method of treating 12-lipoxygenase mediated diseases by administering compounds of Formula (I)
A method of treating diseases mediated by 12-lipoxygenase comprising administering an effective amount of a compound of Formula (I) characterized by specific substituents R1, R2, and R3, where R1 is selected from methoxy and chlorine when R2 is hydrogen, R2 is selected from bromine and chlorine when R1 is hydrogen, and R3 is selected from various heteroaromatic and aromatic groups or their pharmaceutically acceptable salts.
Method involving compounds with defined substitutions for R1, R2, and R3
Substitutions wherein R1 is methoxy and R2 is hydrogen, with R3 optionally substituted phenyl groups as specified, including halogen substitutions such as fluorine, chlorine, and bromine.
Use of compounds of Formulae (II), (III), and (IV) for treatment methods
Methods of treating 12-lipoxygenase mediated diseases by administering compounds of various other formulae (II, III, IV), each having defined substituents, broadening chemical diversity and therapeutic application scope.
Therapeutic applications for treatment of specific diseases
Methods for treating diseases mediated by 12-lipoxygenase including Type 1 and Type 2 diabetes, diabetic kidney disease, diabetic neuropathy, cardiovascular diseases (including congestive heart failure, myocardial infarction, and stroke), thrombosis, heparin-induced thrombocytopenia, anti-phospholipid syndrome, and thrombosis associated with therapeutic or diagnostic monoclonal antibodies.
Defined exemplary compounds for therapeutic use
Claims recite specific compounds disclosed in the invention (including ML355 and other derivatives) as active agents for treatment in the methods of use described, ensuring specific chemical embodiments are covered.
The independent claims cover methods of treating 12-lipoxygenase mediated diseases by administering potent and selective 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives and related compounds defined by multiple chemical formulae. They include detailed substituent definitions and explicitly claim treatments of various diseases involving 12-LOX, indicating a broad protection over both composition and method of use.
Stated Advantages
The compounds display nanomolar potency against 12-LOX with excellent selectivity over related lipoxygenases and cyclooxygenases.
The compounds possess favorable ADME properties and good in vivo pharmacokinetic profiles, including oral bioavailability and stability in physiological conditions.
The compounds are effective in inhibiting platelet aggregation and calcium mobilization, key processes in thrombosis and platelet hemostasis.
The compounds reduce 12-HETE levels in mouse and human beta cells, indicating potential to protect pancreatic β-cells and treat diabetes.
The inhibitors offer a novel therapeutic approach targeting immune-mediated thrombocytopenia and thrombosis such as heparin-induced thrombocytopenia (HIT).
The chemical scaffold is readily amenable to structural modification, enabling optimization and development of potent and selective 12-LOX inhibitors.
Documented Applications
Treatment or prevention of diseases mediated by 12-lipoxygenase including Type 1 and Type 2 diabetes, diabetic kidney disease, diabetic neuropathy, cardiovascular disease (congestive heart failure, myocardial infarction, stroke), thrombosis, heparin-induced thrombocytopenia (HIT), anti-phospholipid syndrome, and thrombosis associated with therapeutic or diagnostic monoclonal antibodies.
Use in reducing PAR4-AP induced platelet aggregation and calcium mobilization in human platelets.
Use in transplantation and xenotransplantation to improve islet survival prior to transplant by ex vivo treatment.
Treatment of various cancers including prostate, colorectal, breast, and lung cancer.
Potential treatment of Alzheimer's disease and non-alcoholic steatohepatitis through inhibition of 12-LOX mediated pathways.
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