Rho kinase inhibitor BA-1049 (R) and active metabolites thereof
Inventors
Rosen, Kenneth M. • Abbinanti, Matthew D. • Ruschel, Joerg • McKerracher, Lisa • Bond Moritz, Lisa
Assignees
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Publication Number
US-10526313-B2
Publication Date
2020-01-07
Expiration Date
Abstract
BA-1049 (R) and its active metabolite are disclosed. Also disclosed are pharmaceutical formulations containing BA-1049 (R) or its active metabolite.
Core Innovation
The document discloses BA-1049(R) and its active hydroxyl metabolite, 1-hydroxy-BA-1049(R), together with related forms including deuterated forms and adipate salts. It positions BA-1049(R) and 1-hydroxy-BA-1049(R) as selective ROCK2 inhibitors for neurological indications and contrasts these compounds with nonselective ROCK inhibitors such as Fasudil.
The problem being addressed is that ROCK2 is described as CNS-associated and as driving pathological cytoskeletal and vascular permeability pathways relevant to neurotrauma and neurovascular disease. The document links these pathways to conditions including stroke, vasospasm after subarachnoid hemorrhage, cerebral aneurysm, spinal cord injury, traumatic brain injury, and cerebral cavernous malformations (CCM).
The document provides rationale and comparative characterization through enantiomer-specific ROCK1/ROCK2 binding, stating that BA-1049(R) shows stronger ROCK2 affinity and potency than BA-1049(S). It also discusses functional inhibition readouts including reduction of ROCK2 activation biomarkers, and it describes parent versus metabolite comparisons, including that the N-oxide metabolite shows little/no ROCK2 inhibition.
Claims Coverage
The provided claim excerpt contains one independent claim. The inventive coverage focuses on a pharmaceutical formulation defined by an adipate salt of a compound with a specified chemical structure, with a dependent refinement specifying a deuterated form.
Adipate salt pharmaceutical formulation of specified chemical structure
A pharmaceutical formulation comprising an adipate salt of a compound of the structure as indicated by the specified chemical structure in the claim text.
Deuterated adipate salt formulation
The pharmaceutical formulation of the adipate salt compound is deuterated.
Across the provided excerpt, the claimed inventive concept is centered on pharmaceutical formulations using an adipate salt form of a specified-structure compound, with dependent coverage limited to deuterated variants.
Stated Advantages
Selectivity for ROCK2 is presented for neurological indications, supported by enantiomer-specific ROCK1/ROCK2 binding and potency comparisons.
The document indicates improved or targeted ROCK2 inhibition via functional reduction of ROCK2 activation biomarkers in described models.
An active hydroxyl metabolite, 1-hydroxy-BA-1049(R), is described as being relevant to ROCK2 inhibition, alongside parent-versus-metabolite comparisons.
Documented Applications
Neurotrauma and neurovascular disease indications including stroke, vasospasm after subarachnoid hemorrhage, cerebral aneurysm, spinal cord injury, and traumatic brain injury are described.
CNS-associated ROCK2 pathway involvement is described in relation to cerebral cavernous malformations (CCM).
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