Use of Sigma-1 receptor agonist compounds
Compositions and methods for the prevention, inhibition, and/or treatment of progressive fibrosis present in various fibroproliferative disorders. Embodiments relate to the use of Sigma-1 receptor agonists for use in the treatment of prevention of progressive fibrosis characterized by the over proliferation of ECM producing cells, e.g. myofibroblasts and by the excessive deposition of ECM components in a medical or disease condition. Preferred Sigma-1 agonists are disclosed.
1. A method for the treatment of progressive fibrosis in a progressively fibrotic eye tissue of a subject by preventing, reversing or inhibiting fibrotic remodeling of the extracellular matrix,
said method comprising administering to the subject an S1R agonist compound in an effective amount sufficient for preventing, reversing or inhibiting fibrotic remodeling of the extracellular matrix to an area of the eye affected by progressive fibrosis,
said S1R agonist compound having the following formula II:
wherein
Q 1 is a Cl or F or a methyl-halogen selected from CH 2 F, CHF 2 CF 3 , CH 2 C 1 , CHCl 2 , CCl 3 , or a methoxy
Q 2 is H, Cl or F,
R 6 is selected from a substituted or unsubstituted C(1-6) alkyl, C(1-6) alkoxy, C(1-6) alkoxy C(1-6) alkyl, C(5-10) aryl,
Y is CH or O, wherein
if Y is O then R 4 is not present,
if Y is CH then R 4 is H, methyl or ethyl,
R 3 is H, methyl or ethyl, or R 3 and R 4 together with the Y-C2 alkyl moiety which they are attached to, may form a saturated or partially unsaturated cyclic group comprising 0 to 2 heteroatom(s) or R 4 and R 3 together form a C(2-4) alkyl bridge,
R 1 and R 2 are independently H, methyl or ethyl,
or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1 wherein
Q 1 is a methyl-halogen selected from CHF 2 , CF 3 , CHCL 2 or CCL 3 ,
Q 2 is H,
R 6 is selected from a substituted or unsubstituted C(1-6) alkoxyalkyl (or C(1-6) dialkyl-ether) or C(1-2) alkoxy C(2-5) alkyl,
Y is CH or O, wherein
if Y is O then R 4 is not present,
if Y is CH then R 4 is H, methyl or ethyl,
R 3 is H or methyl.
3. The method according to claim 1 wherein said compound is fluvoxamine.
4. The method according to claim 1 wherein the subject has a fibroproliferative eye disorder.
5. The method according to claim 4 wherein said fibroproliferative eye disorder is an eye disease in the anterior segment of the eye.
6. The method according to claim 4 wherein said fibroproliferative eye disorder is glaucoma.
7. The method according to claim 6 wherein glaucoma is selected from the group consisting of open angle glaucoma, closed angle glaucoma, primary glaucoma and secondary glaucoma.
8. The method according to claim 4 wherein said fibroproliferative eye disorder is an eye disease related with a fibrosis in the trabecular meshwork.
9. The method according to claim 1 wherein said S1R agonist is administered in a formulation of eye drops.
10. The method according to claim 1 wherein said S1R agonist is administered in a formulation of ointment.
11. The method according to claim 2 wherein the subject has a fibroproliferative eye disorder which is glaucoma and said S1R agonist is administered in a formulation of eye drops.