title: Amino acid derived quinazolines as Rock/PKA inhibitors.
abstract: SAR and lead optimization studies for Rock inhibitors based on amino acid-derived quinazolines are described. Studies demonstrated that these amino acid derived quinazolinones were mainly pan-Rock (I & II) inhibitors. While selectivity against other kinases could be achieved, selectivity for most of these compounds against PKA was not achieved. This is distinct from Rock inhibitors based on non-amino acid derived quinazolinones, where high selectivity against PKA could be obtained.(22) The inhibitors presented here in some cases possessed sub-nanomolar inhibition of Rock, nanomolar potency in ppMLC cell based assays, low to fair cytochrome P-450 inhibition, and good human microsomal stability.
authors: Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, 130 Scripps Way, 2A1, Jupiter, FL 33458, USA.
authors: Sarwat
authors: S
authors: Chowdhury
authors: Yen Ting
authors: YT
authors: Chen
authors: Xingang
authors: X
authors: Fang
authors: Wayne
authors: W
authors: Grant
authors: Jennifer
authors: J
authors: Pocas
authors: Michael D
authors: MD
authors: Cameron
authors: Claudia
authors: C
authors: Ruiz
authors: Li
authors: L
authors: Lin
authors: Hajeung
authors: H
authors: Park
authors: Thomas
authors: T
authors: Schröter
authors: Thomas D
authors: TD
authors: Bannister
authors: Philip V
authors: PV
authors: Lograsso
authors: Yangbo
authors: Y
authors: Feng
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D001665:Binding Sites; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases