Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (Part-II)

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 23; pp. 7113 - 7118
• Main Authors: Sessions, E. Hampton, Chowdhury, Sarwat, Yin, Yan, Pocas, Jennifer R., Grant, Wayne, Schröter, Thomas, Lin, Li, Ruiz, Claudia, Cameron, Michael D., LoGrasso, Philip, Bannister, Thomas D., Feng, Yangbo
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.12.2011; Elsevier
• Subjects: Animals; Antineoplastic agents; Azaindole; Binding Sites; Biological and medical sciences; Cardiovascular system; Cytochrome P-450 Enzyme Inhibitors; Drug Discovery; Enzyme Activation - drug effects; Eye; General aspects; glaucoma; Humans; hypertension; Indole; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Inhibitory Concentration 50; Kinase inhibitor; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Pyrazole; Rats; Rho kinase; rho-Associated Kinases - antagonists & inhibitors; ROCK; Solubility; stroke; Water - chemistry; ROCK; Rho kinase; Kinase inhibitor; Indole; Pyrazole; Azaindole; Intravenous administration; Rat; Non-specific serine/threonine protein kinase; Selectivity; Optimization; Signal transduction; Structure activity relation; Pyrazole derivatives; Water solubility; Enzyme; Transferases; Rodentia; Oral administration; Enzyme inhibitor; In vitro; In vivo; Vertebrata; Mammalia; Animal; Indole derivatives; Pharmacokinetics; Physicochemical properties
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.09.084

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.