title: Synthesis and structure based optimization of 2-(4-phenoxybenzoyl)-5-hydroxyindole as a novel CaMKII inhibitor.
abstract: Based on 2-(4-phenoxybenzoyl)-5-hydroxyindole (2), a novel structural class of CaMKII inhibitors were synthesized and further optimized. The strong acidity of the hydroxyl group and the lipophilic group at the 4 and 6-positions were found to be necessary for strong CaMKII inhibition. Compound 25 was identified as a promising compound with 50-fold more potent inhibitory activity for CaMKII than 2. Compound 25 also showed high selectivity for CaMKII over off-target kinases.
authors.affiliation: Research Division, Dainippon Sumitomo Pharma Co., Ltd, Enoki, Suita, Osaka, Japan. masafumi-komiya@ds-pharma.co.jp
authors.forename: Masafumi
authors.initials: M
authors.lastname: Komiya
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Asano
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Koike
authors.forename: Erina
authors.initials: E
authors.lastname: Koga
authors.forename: Junetsu
authors.initials: J
authors.lastname: Igarashi
authors.forename: Shogo
authors.initials: S
authors.lastname: Nakatani
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isobe
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; C026785:5-hydroxyindole; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2