Inhibitors of Rho associated coiled-coil containing protein kinase
Inventors
Skucas, Eduardas • Liu, Kevin G. • Kim, Ji-In • Poyurovsky, Masha V. • Mo, Rigen • ZHANG, Jingya
Assignees
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Publication Number
US-11479533-B2
Publication Date
2022-10-25
Expiration Date
Abstract
The invention relates to inhibitors of ROCK1 and/or ROCK2. Also provided are methods of inhibiting ROCK1 and/or ROCK2 that are useful for the treatment of disease.
Core Innovation
The invention relates to compounds having formula I and a second formula, wherein A, R1, R10, R11, R12, R13, W, c, d, R2, R3, R4, R5, a, b, and n are defined through specified groups and structural constraints, with alternative cyclization options for R12 and R13 and for R3 and R5. The compounds are optionally in the form of pharmaceutically acceptable salts, and the disclosed variability includes defined substituent sets and ring-size constraints for heterocyclic or heteroaryl groups represented by W.
The disclosed compound scope further includes additional formula embodiments with refined definitions of substituents and index values, including quantitative ranges for c, d, b, and n. Stereo-specific variants, such as (R)/(S) enantiomers, and specified structural alternatives are presented alongside compound embodiments.
The document describes ROCK1/ROCK2 biology and a therapeutic rationale for selective or pan-ROCK inhibition. The invention is directed to inhibitors that act on the Rho-ROCK pathway for therapeutic use, with particular emphasis on central nervous system disorders and blood-brain barrier (BBB) relevant activity.
Claims Coverage
The provided independent claims cover compound families defined by formula I and a second core formula, each with extensive structural substituent and ring constraints and including pharmaceutically acceptable salts. The independent claims also cover methods of treatment for fibrotic disorders, central nervous system disorders, and diseases mediated by ROCK1 or ROCK2. Across the independent claims, the principal inventive features are the specified chemical formulas, their variable definitions, and the therapeutic use of those compounds.
Compound having formula I with defined substituent groups and ring constraints
A compound having the formula I wherein A is selected from the group consisting of specified substituent types; R1 and R11 are selected from specified lower alkyl/cycloalkyl groups; R12 and R13 are selected from specified hydrogen and lower alkyl options with an optional C3-C6 cycloalkyl taken together; W is a 3- to 7-membered heterocyclic or heteroaryl ring having 1 to 3 ring heteroatoms; c is 2 to 4 and d is 1 to 4; R2 is selected from specified aryl/heteroaryl/heterocyclyl groups with defined optional substituents; R3 and R4 are defined with specified option sets; R5 is selected from H, lower alkyl, and C3-C6 cycloalkyl with an alternative where R3 and R5 taken together form an unsubstituted or optionally substituted cyclic group having 5 to 7 ring atoms including 2-3 ring heteroatoms; and a is 0 or 1 and b is 0 to 2, with R and R′ defined as independently selected or alternatively forming a 5 to 6 membered heterocyclic ring; or a pharmaceutically-acceptable salt thereof.
Core formula compound with substituted A, R4, R5, and R21 options including cyclic alternatives
A compound having the formula wherein A is selected from the group consisting of specified lower alkyl substituted options and specified heteroaryl/heterocyclyl or cyclopropyl options; R4 is selected from specified halo/hydroxy/lower alkyl/lower alkoxy/nitro/cyano/perfluoro alkyl/perfluoro alkoxy/carboxyl/amido-like and related options; R5 is hydrogen or lower alkyl; each R21 is selected from specified substituent options with an alternative where two R21 groups taken together form a cyclic group having 5 ring atoms including 2-3 ring heteroatoms with optional substitution; R and R′ are independently selected from H, lower alkyl, and C3-C6 cycloalkyl or alternatively taken together form a 5 to 6 membered heterocyclic ring; b is 0 to 3 and n is 0 to 3; or a pharmaceutically-acceptable salt thereof.
Treating a fibrotic disorder with a formula I compound
A method for treating a fibrotic disorder by administering to a subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Treating a central nervous system disorder with a formula I compound
A method for treating a central nervous system disorder by administering to a subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Treating a disease mediated by ROCK1 or ROCK2 with a formula I compound
A method for treating a disease in a subject mediated by ROCK1 or ROCK2 by administering to a subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Across the independent claims provided, the inventive subject matter is centered on formula I compounds with detailed structural constraints, a second core formula with defined substituent options, and methods that use those compounds for therapeutic treatment in fibrotic disorders, central nervous system disorders, and diseases mediated by ROCK1 or ROCK2.
Stated Advantages
Not explicitly described in patent.
Documented Applications
ROCK functional assay evaluation including Z’-Lyte kinase, In-Cell ELISA (A7R5; ppMLC (T18/S19)), and NIH3T3-Acta2-promoter luciferase for ROCK1/ROCK2 inhibition.
Blood-brain barrier penetration evaluation using brain/plasma ratios by HPLC/MS/MS.
Neurite outgrowth/differentiation in multiple cell/in vivo disease models.
Neuroprotection against Aβ1-42.
Modulation of pro-fibrotic gene expression including Acta2/αSMA, CTGF, and CCN1, and anti-fibrotic efficacy in bleomycin lung fibrosis models (including Ashcroft score and related endpoints).
Endothelial barrier stabilization in a histamine-induced vascular permeability assay, including Evans blue measurements.
Treating fibrotic disorders by administering a therapeutically effective amount of a formula I compound or a pharmaceutically acceptable salt.
Treating central nervous system disorders by administering a therapeutically effective amount of a formula I compound or a pharmaceutically acceptable salt.
Treating a disease mediated by ROCK1 or ROCK2 by administering a therapeutically effective amount of a formula I compound or a pharmaceutically acceptable salt.
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