Phthalazinone-based lactams and cyclic ureas as ROCK2 selective inhibitors

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Rho-kinase (ROCK) signaling is implicated in various diseases, making ROCK inhibitors a therapeutic target.
• Aniline amides are common scaffolds in ROCK inhibitor design, but alternatives are sought for improved properties.
• Phthalazinone derivatives have shown promise as kinase inhibitors.

Purpose of the Study:

• To explore novel replacements for aniline amides in phthalazinone-based ROCK inhibitors.
• To identify potent and selective ROCK2 inhibitors.
• To evaluate the kinase selectivity profile of new compound series.

Main Methods:

• Synthesis of novel phthalazinone derivatives incorporating lactam, cyclic urea, and carbamate moieties.
• In vitro kinase inhibition assays to assess potency against ROCK1 and ROCK2.
• Broad kinase panel screening to determine selectivity profiles.

Main Results:

• Several novel derivatives were synthesized and evaluated as ROCK inhibitors.
• Compound 22 emerged as a potent inhibitor of ROCK2.
• Compound 22 demonstrated excellent overall kinase selectivity and good isoform selectivity over ROCK1.

Conclusions:

• Lactam, cyclic urea, and carbamate derivatives are viable replacements for aniline amides in phthalazinone-based ROCK inhibitors.
• Compound 22 represents a promising lead for the development of selective ROCK2 inhibitors.
• The identified compounds offer potential therapeutic applications by targeting ROCK signaling pathways.