Triazine and pyrimidine based ROCK inhibitors with efficacy in spontaneous hypertensive rat model

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biochemistry

Background:

• Rho-kinase (ROCK) is implicated in various physiological processes, including cell motility and blood pressure regulation.
• Dysregulation of ROCK signaling contributes to diseases like hypertension.
• Developing selective ROCK inhibitors is a therapeutic goal.

Purpose of the Study:

• To design and characterize a novel series of triazine and pyrimidine-based ROCK inhibitors.
• To investigate the structure-activity relationship (SAR) and binding mode of these inhibitors.
• To evaluate the in vitro and in vivo efficacy of the developed compounds.

Main Methods:

• Homology modeling was used to establish an initial binding mode.
• Structure-activity relationship (SAR) studies were conducted.
• Compounds were tested in cell migration assays.
• Kinase selectivity profiling was performed.
• In vivo studies were conducted in a spontaneous hypertensive rat model.

Main Results:

• A series of triazine and pyrimidine-based ROCK inhibitors were synthesized and profiled.
• The binding mode and SAR were consistent with experimental observations.
• Compounds exhibited potent activity in cell migration assays.
• Favorable kinase selectivity was observed for the inhibitors.
• Compound 1A demonstrated significant in vivo activity in a spontaneous hypertensive rat model.

Conclusions:

• The described triazine and pyrimidine scaffolds are effective for developing potent ROCK inhibitors.
• The identified compounds possess desirable kinase selectivity profiles.
• Compound 1A represents a promising candidate for further development in treating hypertension.