title: Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCbeta-selective inhibitors.
abstract: Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki Osaka 569-1125, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanaka
authors.forename: Shoichi
authors.initials: S
authors.lastname: Sagawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Hoshi
authors.forename: Fumito
authors.initials: F
authors.lastname: Shimoma
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Yasue
authors.forename: Minoru
authors.initials: M
authors.lastname: Ubukata
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ikemoto
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hase
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sasase
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ueda
authors.forename: Mutsuyoshi
authors.initials: M
authors.lastname: Matsushita
authors.forename: Takashi
authors.initials: T
authors.lastname: Inaba
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003930:Diabetic Retinopathy / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D008301:Maleimides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D008301:Maleimides; D011493:Protein Kinase C; D064546:Protein Kinase C beta