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

Bioaxone Biosciences Inc

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 disclosure relates to ROCK2-targeting (R)-enantiomer BA-1049 and related solid-state and isotopic variants, including its active metabolite 1-hydroxy-BA-1049(R). It focuses on ROCK2-selective inhibition and on crystalline pharmaceutical compositions comprising an adipate salt of a crystalline form of a compound of Formula I, characterized by an X-ray powder diffraction (XRPD) spectrum having a peak expressed in degrees 2θ (±0.2) of about 12.2.

The disclosure reports preclinical findings consistent with selective ROCK2 activity, including stronger inhibition of ROCK2 pathway activation than racemic BA-1049 and Fasudil, and evidence of ROCK2 binding selectivity (KD) and ROCK2 inhibition potency (IC50) for BA-1049(R). It also describes reduction of phospho-cofilin, reduced phospho-MLC2 including pMLC2 (Ser19), reduced microglial activation as indicated by IBA1, and improved endothelial barrier function with reduced Evans blue extravasation.

The disclosure further includes pharmacokinetic and brain penetration data obtained using LC-MS/MS after IV, IP, and PO administration, together with metabolic profiles showing hepatocyte metabolism to 1-hydroxy-BA-1049(R) and N-oxide-BA-1049(R). It also describes biomarker changes and cellular outcomes associated with endothelial permeability and junction integrity, including actin stress fibers, and provides a deuteration rationale for compound variants.

Claims Coverage

The independent claims cover three aspects: a method of treating cerebral cavernous malformations using an adipate salt crystalline form defined by an XRPD peak at about 12.2° 2θ (±0.2), the crystalline form itself as a product, and a method for treating a neurological condition using pharmaceutical compositions containing therapeutically effective amounts of the crystalline adipate salt of Formula I and/or a compound of Formula II, with the same XRPD constraint. Across the independent claims, the defining technical element is the XRPD-defined crystalline adipate salt.

Overall, the claim set centers on pharmaceutical compositions and crystalline product forms defined by an XRPD peak at about 12.2° 2θ (±0.2) for an adipate salt of Formula I compounds, with therapeutic methods directed to cerebral cavernous malformations and other neurological conditions, including embodiments that also administer a Formula II compound and/or additional rho kinase inhibitors.

Stated Advantages

Documented Applications