title: Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I).
abstract: 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.
authors: Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Sarwat
authors: S
authors: Chowdhury
authors: E Hampton
authors: EH
authors: Sessions
authors: Jennifer R
authors: JR
authors: Pocas
authors: Wayne
authors: W
authors: Grant
authors: Thomas
authors: T
authors: Schröter
authors: Li
authors: L
authors: Lin
authors: Claudia
authors: C
authors: Ruiz
authors: Michael D
authors: MD
authors: Cameron
authors: Stephan
authors: S
authors: Schürer
authors: Philip
authors: P
authors: LoGrasso
authors: Thomas D
authors: TD
authors: Bannister
authors: Yangbo
authors: Y
authors: Feng
mesh_terms: D001665:Binding Sites; D065607:Cytochrome P-450 Enzyme Inhibitors; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C023422:7-azaindole dimer; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D054460:rho-Associated Kinases