Novel Human 12-Lipoxygenase (Lox) Inhibitors

Background

Human Platelet-type 12-(S)-lipoxygenase (12-LOX) is a non-heme iron-containing oxygenase that catalyzes the regio- and stereo-specific addition of molecular oxygen to polyunsaturated fatty acids (PUFA). 12-LOX belongs to a family of enzymes that also include 5- LOX and 15-LOX, which oxygenate arachidonic acid (AA) at their corresponding carbon positions. The hydroperoxyeicosatetraenoic acid (HPETE) product is subsequently reduced by cellular peroxidases to form the hydroxyeicosatetraenoic acid (HETE), which in the case of 12- LOX is 12-(S)-HETE.

Although 12-LOX expression is predominantly restricted to platelets (~14,000 molecules per platelet), it is also expressed in some hematopoietic and solid tumors. To date, 12-LOX is the only LOX isoform identified to be present in platelets, and its activity is part of a number of platelet functions, including granule secretion, platelet aggregation, and normal adhesion through specific agonist-mediated pathways, such as collagen and the thrombin receptor, PAR4. Normal platelet activation plays a central role in the regulation of hemostasis, but uncontrolled activation can lead to pathologic thrombotic events, such as ischemic coronary heart disease.

Technology Description

Compounds of the structure are as provided below:

where R1, R2, R3, R4 and R5 are each independently selected from hydrogen, hydroxy, alkoxy, amine, cyano, thiol, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl,cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; X is S or O; the A ring is a substituted or unsubstituted 5 to 12 membered ring; n is an integer from 0 to 12; and each Ra is independently selected from hydrogen, hydroxy, alkoxy, amine, cyano, thiol, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or a salt, solvate or hydrate thereof.

The predicted binding mode of Compound LOX-12-001 with wt12-LOX is shown below. Residues that interact with the inhibitor are shown. Residues that mutated in the present study are shown in ball-and-stick representation and they are labelled.

Applications

• Treating or preventing an immune-mediated thrombocytopenia or thrombosis disorder. 
• Treating diabetes, type II diabetes, diabetic kidney disease, diabetic nerve disease, cardiovascular disease, non-alcoholic steatohepatitis, platelet hemostasis, heparin-induced thrombocytopenia, thrombosis, Alzheimer’s disease and cancer.

Advantages

Greater specificity and better solubility than other 12-LOX inhbitors. 

Intellectual Property Information

Additional Patents Pending

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