ABSTRACT
Therapeutic interventions with Rho kinase (ROCK) inhibitors may effectively treat several disorders such as hypertension, stroke, cancer, and glaucoma. Herein we disclose the optimization and biological evaluation of potent novel ROCK inhibitors based on substituted indole and 7-azaindole core scaffolds. Substitutions on the indole C3 position and on the indole NH and/or amide NH positions all yielded potent and selective ROCK inhibitors (25, 42, and 50). Improvement of aqueous solubility and tailoring of in vitro and in vivo DMPK properties could be achieved through these substitutions.
Subject(s)
Drug Discovery , Indoles/chemical synthesis , Water/chemistry , rho-Associated Kinases/antagonists & inhibitors , Animals , Binding Sites , Cytochrome P-450 Enzyme Inhibitors , Enzyme Activation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Rats , SolubilityABSTRACT
Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC(50)=1 nM) with 740-fold selectivity over PKA (47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II.
Subject(s)
Drug Discovery , Indoles/chemical synthesis , rho-Associated Kinases/antagonists & inhibitors , Binding Sites , Cytochrome P-450 Enzyme Inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Molecular StructureABSTRACT
Rho kinase (ROCK) is an attractive therapeutic target for various diseases including glaucoma, hypertension, and spinal cord injury. Herein, we report the development of a series of ROCK-II inhibitors based on 4-quinazolinone and quinazoline scaffolds. SAR studies at three positions of the quinazoline core led to the identification of analogs with high potency against ROCK-II and good selectivity over protein kinase A (PKA).
