15Lox1 Inhibitors For Stroke

Background

Stroke is a leading cause of mortality and disability worldwide and the economic costs of treatment and post-stroke care are substantial. Every year, more that 14 million people are affected by stroke, and over 6 million stroke patients die from this condition and associated complications.

2-(2,3,5-trisubstituted phenyl)oxazole compounds potently inhibit 12/15-LOX. Hence, the compounds of this disclosure are advantageously useful to treat or prevent various disorders where 12/15-LOX is implicated in the pathology of the disorder (e.g.,stroke).

Technology Description

 In collaboration with researchers at Partners Healthcare, UCSC Researchers helped develop compounds that inhibit 12/15 Lipoxygenase 

X1 is selected from O and S;

R1, R2, and R3 are each independently selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;

R4 is selected from H, C1-3 alkyl, and HO-C1-3 alkylene;

R5 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)ORa1,C(O)N(Ra1)2, P(=O)(ORa1)2, and C(O)Rb1; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with a substituent selected from ORa1 and OP(=O)(ORa1)2;

each Ra1 is independently selected from H, C1-6 alkyl, C6-10 aryl, C1-6 alkyl-C6-10 aryl, and C1-6 alkyl-C6-10 aryl-C1-6 alkyl, wherein said C1-6 alkyl, C6-10 aryl,

C1-6 alkyl-C6-10 aryl, and C1-6 alkyl-C6-10 aryl-C1-6 alkyl are each optionally substituted with a substituent selected from amino, C1-6 alkylamino, (C1-6 haloalkyl)amino, di(C1-6 alkyl)amino, (C1-6 alkyl)(C1-6 haloalkyl)amino, (C6-10 aryl)amino, (C6-10 aryl)(C1-6 alkyl)amino, (5-6-membered heteroaryl)amino, (5-6-membered heteroaryl)(C1-6 alkyl)amino, C6-10 aryl, 4-6 membered heterocycloalkyl, 5-6-membered heteroaryl, and ORa2, wherein said C6-10 aryl, 4-6 membered heterocycloalkyl, and 5-6-membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from amino, C1-6 alkylamino, di(C1-6 alkyl)amino, carboxy, and halo; each Ra2 is independently selected from H, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy-C1-3 alkyl, 4-7 membered heterocycloalkyl-C1-3 alkyl, 5-6-membered heteroaryloxy-C1-3 alkyl, C6-10 aryl, and 5-6-membered heteroaryl, wherein said C6-10 aryl and 5-6-membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, and C1-3 haloalkyl; and Rb1 is C1-6 alkyl, optionally substituted with a substituent selected from amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and 4-7 membered heterocycloalkyl ring comprising at least one N atom.

In some embodiments, X1 is O.

In some embodiments, X1 is S.

Compounds demonstrated excellent solubility and specificity for 12/15 LOX, metabolic stabilty in human, mouse, and rat liver endosomes, and significant infarct size reduction in an MCAO ischemia/reperfusion injury mouse model as well as improved behavioral outcomes in a subarachnoid hemorrhage mouse model. 

Applications

Treatment of stroke, ischemia reperfusion injury, and subarachnoid hemorrhage. 

Advantages

Improved solubilty and specificity over other 12/15 LOX inhibitors. 

Results demonstrated in animal studies.  

Intellectual Property Information

Additional Patents Pending

Related Materials

• Contributions of 12/15-Lipoxygenase to Bleeding in the Brain Following Ischemic Stroke - 09/28/2019