Kinase inhibitors for treatment of disease
Inventors
Ruschel, Joerg • Abbinanti, Matthew D. • Rosen, Kenneth M. • McKerracher, Lisa
Assignees
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Publication Number
US-10537567-B2
Publication Date
2020-01-21
Expiration Date
Abstract
Disclosed are therapeutic compositions including BA-1076 and/or BA-2057, methods of their use in the treatment of ophthalmological disorders. The therapeutic compositions may further include an IOP-lowering prostaglandin. The methods may further include administration of an IOP-lowering prostaglandin.
Core Innovation
The disclosure describes selective ROCK kinase inhibitors BA-1076 and BA-2057, optionally with Abl, and therapeutic compositions containing BA-1076 and/or BA-2057 with stereochemical enrichment. The compounds are present in at least 10% enantiomeric excess in the therapeutic composition, with preferred embodiments indicating higher enantiomeric excess. The invention is framed around pharmaceutically acceptable compositions for treating disease states described in the ocular context.
The disclosure addresses ocular disease and tissue responses, including glaucoma and associated trabecular meshwork fibrosis that can affect intraocular pressure, as well as retinal ganglion cells protection via reduction of extracellular matrix deposition and fibrosis. It further identifies retinal conditions and vascular activity, including retinitis pigmentosa, macular degeneration, and retinal angiogenesis, as therapeutic targets. Ocular indications also include corneal blindness, Fuchs’ corneal dystrophy, and corneal scarring.
The compositions are described with ocular suitability in mind, including administration routes such as topical eye drops and intraocular administration options, as well as systemic options including oral and intravenous administration. Co-therapy with IOP-lowering prostaglandin analogs can be used, including Travaprost, Bimatoprost, Latanoprost, and Tafluprost. The disclosure also states that BA-1076 and/or BA-2057 lack the GRK1-related off-target profile associated with metabolites from BA-1049.
Claims Coverage
The partial claim set includes two independent claims covering therapeutic compositions containing stereochemically enriched BA-1076 or BA-2057 at a minimum enantiomeric excess of at least 10%. Across the independent claims, two principal inventive features are present: stereochemical enrichment for a selected ROCK/Abl inhibitor and use of the composition in specified ocular treatment contexts.
Therapeutic composition with stereochemically enriched BA-1076
A therapeutic composition comprising a therapeutically effective amount of a compound of formula or a pharmaceutically acceptable salt thereof, wherein BA-1076 or a pharmaceutically acceptable salt thereof is present in at least 10% enantiomeric excess.
Therapeutic composition with stereochemically enriched BA-2057
A therapeutic composition comprising a therapeutically effective amount of a compound of formula or a pharmaceutically acceptable salt thereof, wherein BA-2057 or a pharmaceutically acceptable salt thereof is present in at least 10% enantiomeric excess.
Overall, the independent claims cover composition-level protection via stereochemical enrichment for BA-1076 or BA-2057, respectively. The dependent claims described in the partial content further align these compositions with ocular treatment indications and optionally include co-administration of named prostaglandin analogs, while also enumerating possible ocular and systemic administration routes.
Stated Advantages
Improved ocular suitability via reduced hyperemia potential.
Off-target selectivity, including that BA-1076/BA-2057 lack a GRK1-related off-target profile attributed to metabolites from BA-1049.
Documented Applications
Treating glaucoma by administering a therapeutically effective amount of the therapeutic composition to a subject in need.
Treating retinitis pigmentosa by administering a therapeutically effective amount of the therapeutic composition to a subject in need.
Treating macular degeneration by administering a therapeutically effective amount of the therapeutic composition to a subject in need.
Treating retinal angiogenesis by administering a therapeutically effective amount of the therapeutic composition to a subject in need.
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