INHIBITORS OF OXIDIZED LOW-DENSITY LIPOPROTEIN RECEPTOR 1 AND METHODS OF USE THEREOF
Inhibitors of oxidized low-density lipoprotein receptor 1 (LOX-1), compositions comprising inhibitors of LOX-1, and methods of using thereof are described.
1 . A compound, the compound comprising Formula (I):
wherein:
X is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfone, and nitrogen;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, aldehyde, haloformyl, hydroperoxyl, halogen, amino, phosphor, sulfhydryl, sulfino, sulfa, C 1 -C 5 alkyl, cyano, and halogen, with the proviso that when Y 1 is nitrogen, R 4 is absent and/or when Y 2 is nitrogen R 3 is absent;
R 5 independently in each occurrence is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, aldehyde, haloformyl, hydroperoxyl, halogen, amino, phosphor, sulfhydryl, sulfino, sulfa, C 1 -C 6 alkyl, cyano, and halogen; and n is an integer from 1 to 10.
2 . The compound of claim 1 , the compound comprising Formula (I), wherein: X is selected from the group consisting of oxygen and sulfur;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydroxyl, aldehyde, haloformyl, hydroperoxyl, alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, halogen, amino, phosphor, sulfhydryl, sulfino, sulfa and cyano;
R 5 independently in each occurrence is selected from the group consisting of hydrogen, hydroxyl, aldehyde, haloformyl, hydroperoxyl, halogen, amino, phosphor, sulfhydryl, sulfino, sulfa and cyano; and
n is an integer from 1 to 6.
3 . The compound of claim 2 , wherein R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen.
4 . The compound of claim 1 , the compound comprising Formula (I), wherein: X is selected from the group consisting of oxygen and sulfur;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, amine, aminoalkyl, halogen and cyano;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen;
R 5 independently in each occurrence is selected from the group consisting of hydrogen, hydroxyl, and alkyloxy; and n is an integer from 1 to 6.
5 . The compound of claim 1 , the compound comprising Formula (I), wherein: X is selected from the group consisting of oxygen and sulfur;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, aminoalkyl, and amino;
R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
R 3 is selected from the group consisting of absent, hydrogen, C 1 -C 6 alkyl, halogen and cyano;
R 4 is selected from the group consisting of absent, hydrogen, C 1 -C 6 alkyl and halogen;
R 5 independently in each occurrence is selected from the group consisting of hydrogen and hydroxyl;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen; and n is 3.
6 . The compound of claim 1 , the compound comprising Formula (I), wherein: X is oxygen;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, aminoalkyl, and amino;
R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
R 3 is selected from the group consisting of absent, hydrogen, C 1 -C 6 alkyl, halogen and cyano;
R 4 is selected from the group consisting of absent, hydrogen, C 1 -C 6 alkyl and halogen;
R 5 independently in each occurrence is selected from the group consisting of hydrogen and hydroxyl;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen; and n is 3.
7 . The compound of claim 1 , the compound comprising Formula (I), wherein: X is oxygen;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, aminoalkyl, and amino;
R 2 is selected from the group consisting of hydrogen, methyl and ethyl; R 3 is selected from the group consisting of absent, hydrogen, methyl, ethyl, propyl, halogen and cyano;
R 4 is selected from the group consisting of absent, hydrogen, methyl, ethyl and halogen;
R 5 independently in each occurrence is selected from the group consisting of hydrogen and hydroxyl;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen; and n is 3.
8 . The compound of claim 1 , the compound comprising Formula (I), wherein: X is oxygen;
Y 1 is nitrogen and Y 2 is carbon;
R 1 is selected from the group consisting of methyl, ethyl, propyl, aminoalkyl, and amino;
R 2 is selected from the group consisting of hydrogen, methyl and ethyl;
R 3 is selected from the group consisting of methyl, ethyl, propyl, halogen and cyano;
R 4 is absent;
R 5 independently in each occurrence is selected from the group consisting of hydrogen and hydroxyl;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen; and n is 3.
9 . The compound of claim 1 , the compound comprising Formula (I), wherein: X is oxygen;
Y 1 is carbon and Y 2 is nitrogen;
R 1 is hydrogen;
R 2 is selected from the group consisting of hydrogen and methyl;
R 3 is absent;
R 4 is selected from the group consisting of hydrogen, methyl, ethyl and halogen;
R 5 independently in each occurrence is selected from the group consisting of hydrogen and hydroxyl;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen; and n is 3.
10 . The compound of claim 1 , the compound comprising Formula (II):
wherein:
X is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfone, and nitrogen;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, aldehyde, haloformyl, hydroperoxyl, halogen, amino, phosphor, sulfhydryl, sulfino, sulfa, C 1 -C 6 alkyl, and cyano, with the proviso that when Y 1 is
nitrogen, R 4 is absent and/or when Y 2 is nitrogen R 3 is absent;
R 5 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, aldehyde, haloformyl, hydroperoxyl, halogen, amino, phosphor, sulfhydryl, sulfino, sulfa, C 1 -C 6 alkyl and cyano.
11 . The compound of claim 10 , the compound comprising Formula (II), wherein: X is selected from the group consisting of oxygen and sulfur;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydroxyl, aldehyde, haloformyl, hydroperoxyl, alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, halogen, amino, phosphor, sulfhydryl, sulfino, sulfa and cyano; and
R 5 is selected from the group consisting of hydrogen, hydroxyl, aldehyde, haloformyl, hydroperoxyl, halogen, amino, phosphor, sulfhydryl, sulfino, sulfa and cyano.
12 . The compound of claim 11 , wherein R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen.
13 . The compound of claim 10 , the compound comprising Formula (II), wherein: X is selected from the group consisting of oxygen and sulfur;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, amine, aminoalkyl, halogen and cyano;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen; and
R 5 is selected from the group consisting of hydrogen, hydroxyl, and alkyloxy.
14 . The compound of claim 10 , the compound comprising Formula (II), wherein:
X is selected from the group consisting of oxygen and sulfur;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, aminoalkyl, and amino;
R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
R 3 is selected from the group consisting of absent, hydrogen, C 1 -C 6 alkyl, halogen and cyano;
R 4 is selected from the group consisting of absent, hydrogen, C 1 -C 6 alkyl and halogen;
R 5 is selected from the group consisting of hydrogen and hydroxyl; and
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen.
15 . The compound of claim 10 , the compound comprising Formula (II), wherein: X is oxygen;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, aminoalkyl, and amino;
R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
R 3 is selected from the group consisting of absent, hydrogen, C 1 -C 6 alkyl, halogen and cyano;
R 4 is selected from the group consisting of absent, hydrogen, C 1 -C 6 alkyl and halogen;
R 5 is selected from the group consisting of hydrogen and hydroxyl; and
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen.
16 . The compound of claim 10 , the compound comprising Formula (II), wherein: X is oxygen;
Y 1 and Y 2 are independently selected from the group consisting of carbon and nitrogen;
R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, aminoalkyl, and amino;
R 2 is selected from the group consisting of hydrogen, methyl and ethyl; R 3 is selected from the group consisting of absent, hydrogen, methyl, ethyl, propyl, halogen and cyano;
R 4 is selected from the group consisting of absent, hydrogen, methyl, ethyl and halogen;
R 5 is selected from the group consisting of hydrogen and hydroxyl; and
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and halogen.
17 .- 23 . (canceled)
24 . A pharmaceutical composition, the composition comprising a compound of claim 1 .
25 . A method of inhibiting oxidized low-density lipoprotein receptor 1 (LOX-1), the method comprising contacting LOX-1 with a compound of claim 1 .
26 . (canceled)
27 . The method of claim 25 , wherein inhibiting LOX-1 inhibits LOX-1-mediated uptake of ox-LDL.
28 . The method of claim 25 , wherein inhibiting LOX-1 inhibits intracellular signaling of LOX-1.
29 .- 39 . (canceled)