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US 2025/0170143 A1Published application
Methods of treating ocular fibrotic pathologies
AssigneeMayo Foundation for Medical Education and Research
InventorsAndrew J. Haak, Sophie Bakri
Life of this patent
Estimating the term…
Abstract
The present application provides compounds and methods for treating ocular fibrotic pathologies, including using dopamine D2 receptor antagonists for treating proliferative vitreoretinopathy.
Claims19
A method of treating or preventing an ocular fibrotic pathology, the method comprising administering to a subject in need thereof a therapeutically effective amount of (a) a dopamine receptor D2 (DRD2) antagonist, or a pharmaceutically acceptable salt thereof, (b) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or (c) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,
- wherein Formula (I) is:
- wherein:
- X1 is selected from O, S, CH2, and NRN;
- X2 is selected from O, S, and NRN;
- RN is selected from H, C1-3 alkyl, and C1-3 haloalkyl;
- ring A is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RA;
- each RA is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- ring B is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RB;
- and
- each RB is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- provided that at least one of ring A and ring B is 5-6-membered heteroaryl;
- and
- wherein Formula (II) is:
- wherein:
- X1 is selected from O, S, CH2, and NRN;
- X2 is selected from O, S, CH2, and NRN;
- X3 is selected from O, S, and NRN;
- ring A is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RA;
- each RA is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- ring B is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RB;
- and
- each RB is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino.
19 more elements
A method selected from the group consisting of:
- (a) inhibiting epithelial to mesenchymal transition (EMT) in a retinal pigment epithelial (RPE) cell,
- (b) inhibiting migration or proliferation of a retinal pigment epithelial (RPE) cell,
- (c) inhibiting expression of a profibrotic gene in a retinal pigment epithelial (RPE) cell,
- (d) inhibiting extra-cellular matrix production and deposition by a retinal pigment epithelial (RPE) cell, and
- (e) enhancing extra-cellular matrix degradation by a retinal pigment epithelial (RPE) cell,
- wherein the method comprises contacting the cell with an effective amount of (a) a dopamine receptor D2 (DRD2) antagonist, or a pharmaceutically acceptable salt thereof, (b) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or (c) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,
- wherein Formula (I) is:
- wherein:
- X1 is selected from O, S, CH2, and NRN,
- X2 is selected from O, S, and NRN,
- RN is selected from H, C1-3 alkyl, and C1-3 haloalkyl;
- ring A is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RA;
- each RA is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- ring B is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RB;
- and
- each RB is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- provided that at least one of ring A and ring B is 5-6-membered heteroaryl;
- and
- wherein Formula (II) is:
- wherein:
- X1 is selected from O, S, CH2, and NRN;
- X2 is selected from O, S, CH2, and NRN;
- X3 is selected from O, S, and NRN;
- ring A is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RA;
- each RA is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- ring B is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RB;
- and
- each RB is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino.
25 more elements
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- X1 is selected from O, S, CH2, and NRN;
- X2 is selected from O, S, and NRN;
- RN is selected from H, C1-3 alkyl, and C1-3 haloalkyl;
- ring A is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RA;
- each RA is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- ring B is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RB;
- and
- each RB is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- provided that at least one of ring A and ring B is 5-6-membered heteroaryl.
7 more elements
A compound of Formula (II):
- or a pharmaceutically acceptable salt thereof, wherein:
- X1 is selected from O, S, CH2, and NRN;
- X2 is selected from O, S, CH2, and NRN;
- X3 is selected from O, S, and NRN;
- ring A is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RA;
- each RA is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;
- ring B is selected from phenyl and 5-6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents independently selected from RB;
- and
- each RB is independently selected from halo, CN, OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with OH, C1-3 alkoxy, SH, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino.
6 more elements
19-26. (canceled)
Dependencies are inferred from the claim text.