Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCbeta-selective inhibitors.
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.
Tanaka
Masahiro
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki Osaka 569-1125, Japan.
Sagawa
Shoichi
S
Hoshi
Jun-ichi
J
Shimoma
Fumito
F
Yasue
Katsutaka
K
Ubukata
Minoru
M
Ikemoto
Tomoyuki
T
Hase
Yasunori
Y
Takahashi
Mitsuru
M
Sasase
Tomohiko
T
Ueda
Nobuhisa
N
Matsushita
Mutsuyoshi
M
Inaba
Takashi
T
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
D008301:Maleimides; D011493:Protein Kinase C; D064546:Protein Kinase C beta