Compositions and methods for treating and diagnosing ocular disorders
AssigneeTranslatum Medicus Inc.
InventorShelley Romayne BOYD
Life of this patent
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Abstract
Disclosed herein are methods, compounds, and compositions that are useful for the diagnosis, treatment, or prevention of an ocular disorder, including in the discovery of agents that are efficacious against these disorders.
Claims35
A method for treating or preventing an ocular disorder, comprising administering to a subject in need thereof an effective amount of a compound of Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein
- A may be a bond σ, —X1— or —X1—O—X2—, in which
- X1 and X2, which may be identical or different from each other, may be an alkyl group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms,
- Y is H when A is a bond σ, or Y may be H, —OH, or —N(R11)(R12), when A is —X1— or —X1—O—X2—, in which
- R11 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
- R12 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11 forms a 4- to 7-membered heterocycle,
- R1 and R2, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms,
- R3, R4 and R8, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro and trifluoromethyl;
- with R′ and R″, which may be identical or different from each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms,
- R5 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R)(R″), —N(R′)COR″, nitro and trifluoromethyl, or R5 together with one from between R6 and R7 forms a ring having 5 or 6 carbon atoms;
- with R′ and R″, which may be identical or different from each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms, and
- R6 and R7, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or together form a group C═O, or one from between R6 and R7, together with R5, forms a ring having 5 or 6 carbon atoms, and a pharmaceutically acceptable carrier or excipient.
The method of any one of the above claims, wherein the compound targets macrophages.
The method of any one of the above claims, wherein the compound modulates M1 macrophage activity in the subject.
The method of any one of the above claims, wherein the compound modulates M2 macrophage activity in the subject.
The method of any one of the above claims, wherein the compound is a MCP-modulating agent.
The method of any one of the above claims, wherein the compound differentially targets the proximal and/or distal regulatory region of the MCP-1 gene.
The method of any one of the above claims, wherein the compound is a small molecule with an indazole core.
The method of any one of the above claims, wherein the ocular disorder is one or more of dry age-related macular degeneration (AMD), reticular drusenoid disease (RPD), white-dot syndromes (e.g. serpiginous chorioretinopathy, serpiginous retinopathy, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS), acute zonal occult outer retinopathy (AZOOR), punctate inner choroidopathy (PIC), diffuse subretinal fibrosis (DSF)), late onset retinal degeneration (LORDs), and central serous retinopathy (CSR).
The method of any one of the above claims, wherein the ocular disorder is one or more of a diabetic eye disease (e.g. diabetic retinopathy and DME), Vogt-Kayanagi-Harada disease (VKH), Sarcoid uveitis, Ocular histoplasmosis, Presumed Ocular Histoplasmosis Syndrome, Autoimmune uveitis, Uveitis associated with systemic diseases (e.g. lupus), Crohn's disease, rheumatoid arthritis, and other diseases of known immune origin, Posterior uveitis, Anterior uveitis (e.g. iritis), Bechet's disease, Polyarteritis nodosa, and Wegener granulomatosis.
The method of any one of the above claims, wherein the subject has abnormal expression or activity of one or more of CD64, IDO, SOCS1, CXCL10 Marco, Nos2, II12b, Ptgs2 (Cox2), II23a (II23p19), Ido1, Adipoq, Ccl20, IL17 (subtype a) Ccl5, CD163, Cx3Cr1, FasIg, Gfap, Csf2, Icam1, Ifng, II10, II12b, II13, II17, II18, II1b, II22, II4, II6, Klf4, Mrc1, Myd88, Nlrp3, Ppary, Tgfb1, Tlr4, Tnf, Vcam1, Ccl2, Ccl5, Ccl7, Ccr2, Socs1, Socs3, Stat1, Stat3, and Stat6.
The method of any one of the above claims, wherein the subject is not undergoing treatment with and/or is unresponsive to one or more of an anti-factor D antibody (e.g. lampalizumab (Genentech)), an anti-β-amyloid (anti-Aβ) antibody (e.g. GSK933776 (GSK)), a corticosteroid (e.g. fluocinolone acetonide), MC-1101 (MacuCLEAR), a CD34+ stem cell therapy, an anti-VEGF antibody (e.g. Ranibizumab), brimonidine (Alphagan), an anti-C5 complement antibody (e.g. LFG316 (Novartis), doxycycline (ORACEA), emixustat hydrochloride, sirolimus (RAPAMUNE), and glatiramer acetate (COPAXONE).
The method of any one of the above claims, wherein the subject has evidence of AMD as confirmed by the presence of at least 1 druse greater than about 125 μm in diameter.
The method of any one of the above claims, wherein the subject has no evidence of prior or active choroidal neovascularization (CNV).
The method of any one of the above claims, wherein the subject has one or more well-demarcated GA lesions of a total area of about 2 to about 20 mm2 in one or more eye.
The method of any one of the above claims, wherein the subject has a best-corrected visual acuity score of greater than about 35 letters or a Snellen VA equivalent of about 20/200 or better.
The method of any one of the above claims, wherein the subject has a GA lesion of less than one disc area up to more than 10 disc areas.
The method of any one of the above claims, wherein the subject has early or late stage dry macular degeneration as evidenced by several small drusen or a few medium-sized drusen.
The method of any one of the above claims, wherein the subject has early or late stage dry macular degeneration as evidenced by a large number of medium-sized drusen or one or more large drusen.
The method of any one of the above claims, wherein the subject has early or late stage dry macular degeneration as evidenced by several large drusen and/or an extensive breakdown of cells in the macula.
The method of any one of the above claims, wherein the method further comprises administering an additional therapeutic agent.
The method of any one of the above claims, wherein the subject is a human.
The method of any one of the above claims, wherein the administering is effected orally or intra-vascularly.
The method of any one of the above claims, wherein the administering is effected intraocularly or to the ocular surface.
The method of any one of the above claims, wherein the treatment results in a reduction in the rate of formation, growth or expansion of patches of ocular tissue atrophy or patches of tissue loss.
The method of any one of the above claims, wherein the treatment comprises treating, preventing, or reducing the rate of pathogenesis of the ocular disorder.
A method of treating diabetic retinopathy, comprising administering to a subject in need thereof an effective amount of a compound of Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein
- A may be a bond σ, —X1— or —X1—O—X2—, in which
- X1 and X2, which may be identical or different from each other, may be an alkyl group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms,
- Y is H when A is a bond σ, or Y may be H, —OH, or —N(R11)(R12), when A is —X1— or —X1—O—X2—, in which
- R11 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
- R12 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11 forms a 4- to 7-membered heterocycle,
- R1 and R2, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms,
- R3, R4 and R8, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro and trifluoromethyl;
- with R′ and R″, which may be identical or different from each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms,
- R5 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R)(R″), —N(R′)COR″, nitro and trifluoromethyl, or R5 together with one from between R6 and R7 forms a ring having 5 or 6 carbon atoms;
- with R′ and R″, which may be identical or different from each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms, and
- R6 and R7, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or together form a group C═O, or one from between R6 and R7, together with R5, forms a ring having 5 or 6 carbon atoms.
A method of treating dry age-related macular degeneration (AMD) or reticular pseudodrusen disease (RPD), comprising administering to a subject in need thereof an effective amount of a compound of Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein
- A may be a bond σ, —X1— or —X1—O—X2—, in which
- X1 and X2, which may be identical or different from each other, may be an alkyl group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms,
- Y is H when A is a bond σ, or Y may be H, —OH, or —N(R11)(R12), when A is —X1— or —X1—O—X2—, in which
- R11 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
- R12 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11 forms a 4- to 7-membered heterocycle,
- R1 and R2, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms,
- R3, R4 and R8, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro and trifluoromethyl;
- with R′ and R″, which may be identical or different from each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms,
- R5 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R)(R″), —N(R′)COR″, nitro and trifluoromethyl, or R5 together with one from between R6 and R7 forms a ring having 5 or 6 carbon atoms;
- with R′ and R″, which may be identical or different from each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms, and
- R6 and R7, which may be identical or different from each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, or together form a group C═O, or one from between R6 and R7, together with R5, forms a ring having 5 or 6 carbon atoms;
- and
- a complement factor D inhibitor.
Dependencies are inferred from the claim text.