Pharmacological characterization of a highly selective Rho kinase (ROCK) inhibitor and its therapeutic effects in experimental pulmonary hypertension.

Abstract

Studies on the role of Rho-associated protein kinase (ROCK) in experimental pulmonary artery hypertension (PAH) relies mainly on the use of pharmacological inhibitors. However, interpreting these data is hampered by the lack of specificity of commonly utilized inhibitors. To fill this gap, we have selected and characterized a novel ROCK inhibitor, Compound 3, previously described in a patent. Inhibitory potency of Compound 3 against enzymatic activity of ROCK-1 and 2 (IC50 = 10 ± 3.1 and 7.8 ± 0.5 nM, respectively) was accompanied by a strong vasodilating effect in phenylephrine pre-contracted isolated rat pulmonary artery rings (IC50 = 51.7 ± 9.1 nM) as well as in aortic rings (IC50 = 45.5 ± 1.1 nM). Compound 3 showed a remarkable selectivity towards ROCK 1 and 2 when tested against a large panel (>400) of human kinases. A partial explanation for its selectivity is provided from docking simulations within ROCK-1. Pharmacokinetic studies showed that Compound 3 is suitable for a twice daily administration without significant accumulation upon repeated dosing. In rats with monocrotaline (MCT)-induced pulmonary hypertension, therapy with Compound 3, (1 and 3 mg/kg, s.c., b.i.d.), started 14 days after induction of the disease, attenuated right ventricle systolic pressure (RVSP) increase. Morphometric histological analysis showed that Compound 3, at both doses, counteracted MCT-induced medial thickening of lung distal arterioles with an effect comparable to macitentan (10 mg/kg, p.o., q.d.). Compound 3 is a potent and highly selective ROCK inhibitor that ameliorates hemodynamic parameters and counteracts pulmonary vascular remodeling in experimental PAH.

• Authors: Silvia Cantoni, Stefano Cavalli, Fiorella Pastore, Alessandro Accetta, Daniele Pala, Fabio Vaccaro, Nicola Cesari, Francesco De Logu, Romina Nassini, Gino Villetti, Fabrizio Facchinetti
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 850 Pg. 126-134 (May 05 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 30753868 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Endothelin Receptor Antagonists
• Protein Kinase Inhibitors
• rho-Associated Kinases

Topics

• Animals
• Aorta (drug effects, pathology, physiopathology)
• Endothelin Receptor Antagonists (pharmacology)
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (drug therapy, metabolism, pathology, physiopathology)
• Molecular Docking Simulation
• Protein Conformation
• Protein Kinase Inhibitors (metabolism, pharmacokinetics, pharmacology, therapeutic use)
• Pulmonary Artery (drug effects, pathology, physiopathology)
• Rats
• Tissue Distribution
• Vascular Remodeling (drug effects)
• Vasodilation (drug effects)
• rho-Associated Kinases (antagonists & inhibitors, chemistry, metabolism)