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-11198680-B2
Publication Date
2021-12-14
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 invention relates to BA-1049 (R), its active metabolite 1-hydroxy-BA-1049 (R), and related deuterated forms and adipate salt forms, as selective ROCK2 inhibitors. The disclosure states that these compounds preferentially bind and inhibit ROCK2 over ROCK1, based on binding and inhibitory potency comparisons, with comparative data described against Fasudil, SLx-2119 (KD-025), and racemic BA-1049.
The document reports in vivo stroke-model data showing reduced ROCK2 activation markers after administration following MCAO, including phospho-cofilin and phospho-MLC2 (pMLC2). It also reports reduction of microglial activation using Iba-1 and reduced ischemia-associated endothelial permeability assessed by Evans blue-albumin leakage, together with downstream endothelial biomarker findings and reversal of endothelial permeability.
The disclosure provides a rationale that inhibiting ROCK2 can reverse ROCK activation in brain endothelial cells and promote neurite outgrowth after neurotrauma. It further describes therapeutic use in neurological conditions, including stroke, vasospasm after subarachnoid hemorrhage, cerebral cavernous malformations, cerebral aneurysms, spinal cord injury, and traumatic brain injury, with in vivo supporting outcomes, brain penetration, and therapeutic dosing concepts.
Claims Coverage
The provided claim set contains one independent claim. The independent claim is directed to treating stroke by administering a therapeutically effective amount of a pharmaceutical formulation comprising a compound of a specified structure, or a salt thereof, and one dependent refinement requires that the compound is deuterated.
Treating stroke by administering a specified-structure compound or salt
A method of treating stroke comprising administering to a patient a therapeutically effective amount of a pharmaceutical formulation comprising a compound of the specified structure, or a salt thereof.
Using a deuterated compound
The compound used in the method is deuterated.
The inventive subject matter centers on treating stroke through administration of a pharmaceutical formulation containing a specified-structure compound or salt, with a refinement to a deuterated form.
Stated Advantages
Selective ROCK2 inhibition over ROCK1, as described by comparative binding and inhibitory potency data.
Reduces ROCK2 activation markers (phospho-cofilin and phospho-MLC2) after MCAO.
Reduces microglial activation (Iba-1) and ischemia-associated endothelial permeability (Evans blue-albumin leakage).
More effective than racemic BA-1049 and more effective than Fasudil for ROCK2 activation markers.
Promotes neurite outgrowth after neurotrauma.
Demonstrates minimal effective dose (1 mg/kg).
No observed adverse effects in 2-week daily dosing reported.
Pharmacodynamic duration with efficacy approximately 24 hr is reported.
Prevention with pre-exposure is reported.
Reports brain penetration and pharmacokinetic support across IV, IP, and PO routes using LC-MS/MS.
Documented Applications
Treatment of stroke in vivo, including a stroke model using MCAO, with biomarker evaluation of ROCK2 activation, microglial activation, and ischemia-associated endothelial permeability.
Stroke treatment, including vasospasm after subarachnoid hemorrhage.
Cerebral cavernous malformations (CCMs).
Cerebral aneurysms.
Spinal cord injury.
Traumatic brain injury (TBI).
Cell system assessment including neurite outgrowth potency in NG108 cells, with comparisons to BA-1049 (S) and ROCK inhibitor SLx-2119.
Injury models described as CNS injury and peripheral nerve injury models, including CNS/peripheral regeneration effects linked to PTEN-silencing and ROCK2 expression.
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