Identificação de novos inibidores de RHO kinase planejados como análogos estruturais do prototipo J0P

Abstract

Rho kinases (Rho-associated protein kinases - ROCK) are protein kinases involved in multiple biological processes. Given the accelerated aging of the global population, the development of ROCK inhibitors offers promising perspectives for interventions aimed at effectively managing age-related diseases. This work presents the synthesis and enzymatic evaluation of novel N-acylhydrazonebased ROCK inhibitors designed using aza-vinylogous principles. All synthesized compounds were assessed for their inhibitory profiles against both ROCK isoforms (ROCK1 and ROCK2), and their potential binding modes were explored through molecular dynamics simulations, particularly focusing on ROCK2. Additionally, the pharmacodynamic properties of the sixteen synthesized compounds were evaluated, including kinetic solubility at pH 7.4, chemical stability under gastric and plasma pH conditions, and permeability across the gastrointestinal tract and the blood-brain barrier. Among the sixteen compounds, LASSBio-2346, LASSBio-2348, LASSBio-2350, and LASSBio-2354 exhibited solubility above 50 µM at 4 and 24 hours, high in vitro gastrointestinal permeability, positive blood-brain barrier permeability, and stability under plasma pH conditions. These results guide further studies in disease models affecting the central nervous system associated with aging, such as Alzheimer's and Parkinson's diseases.