Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Rho kinases (ROCK1 and ROCK2) are serine/threonine kinases regulating cellular functions like motility and contraction.
• ROCK inhibitors are therapeutically relevant for conditions including hypertension, glaucoma, and erectile dysfunction.

Purpose of the Study:

• To identify and optimize potent and selective inhibitors of ROCK1 and ROCK2.
• To develop novel drug candidates for diseases involving cellular migration and contraction.

Main Methods:

• High-throughput screening identified initial ROCK1 inhibitor (compound 4).
• Systematic structure-activity relationship (SAR) studies and structure-based design were employed.
• Optimization focused on improving inhibition potency, kinase selectivity, and reducing CYP inhibition.

Main Results:

• Systematic optimization yielded potent and selective ROCK inhibitors.
• Compound 37 demonstrated significant enhancements in inhibition potency and kinase selectivity.
• Compound 37 exhibited reduced CYP inhibition and favorable pharmacokinetics for in vivo studies.

Conclusions:

• Novel ROCK inhibitors were successfully developed through medicinal chemistry efforts.
• Compound 37 represents a promising candidate for further preclinical development in ROCK-related diseases.
• The findings support the therapeutic potential of targeting ROCK kinases.