Synthesis and biological evaluation of 4-quinazolinones as Rho kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 6; pp. 1844 - 1848
• Main Authors: Fang, Xingang, Chen, Yen Ting, Sessions, E. Hampton, Chowdhury, Sarwat, Vojkovsky, Tomas, 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 15.03.2011; Elsevier
• Subjects: Biological and medical sciences; Cardiovascular system; Eye; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protein kinase A; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrazole; Quinazolinone; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacology; Rho kinase; rho-Associated Kinases - antagonists & inhibitors; ROCK inhibitor; Structure-Activity Relationship; Protein kinase A; Quinazolinone; ROCK inhibitor; Rho kinase; Pyrazole; Rat; Enzyme; Transferases; Quinazoline derivatives; Non-specific serine/threonine protein kinase; Rodentia; Oral administration; Enzyme inhibitor; Selectivity; In vitro; In vivo; Signal transduction; Vertebrata; Mammalia; Structure activity relation; Animal; Pyrazole derivatives; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.039

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).