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.
Subject(s)
Maleimides/chemistry , Maleimides/pharmacology , Protein Kinase C/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Diabetes Mellitus, Experimental/drug therapy , Diabetic Retinopathy/drug therapy , Dose-Response Relationship, Drug , Maleimides/pharmacokinetics , Maleimides/therapeutic use , Molecular Structure , Protein Kinase C/metabolism , Protein Kinase C beta , Rats , Structure-Activity RelationshipABSTRACT
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.
Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Isoquinolines/chemical synthesis , Piperidines/chemical synthesis , Pyridines/chemical synthesis , Tetrahydroisoquinolines/chemical synthesis , Administration, Oral , Animals , Arterial Occlusive Diseases/complications , Brain Infarction/drug therapy , Brain Infarction/etiology , Brain Infarction/pathology , Cerebral Arterial Diseases/complications , Factor Xa/chemistry , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Injections, Intravenous , Isoquinolines/chemistry , Isoquinolines/pharmacology , Macaca fascicularis , Middle Cerebral Artery , Models, Molecular , Piperidines/chemistry , Piperidines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Structure-Activity Relationship , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/pharmacology , Venous Thrombosis/drug therapyABSTRACT
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against FXa and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis.
Subject(s)
Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Tetrahydroisoquinolines/pharmacology , Animals , Rats , Serine Proteinase Inhibitors/therapeutic use , Tetrahydroisoquinolines/therapeutic use , Venous Thrombosis/drug therapy , Venous Thrombosis/enzymologyABSTRACT
We report herein synthesis of PKCbeta-selective inhibitors possessing the novel pharmacophore of anilino-monoindolylmaleimide. Several compounds of this series exhibited IC50's as low as 50 nM against human PKCbeta2. One of the most potent compounds, 6l, inhibited PKCbeta1 and PKCbeta2 with IC50 of 21 and 5 nM, respectively, and exhibited selectivity of more than 60-fold in favor of PKCbeta2 relative to other PKC isozymes (PKCalpha, PKCgamma, and PKCepsilon).
Subject(s)
Aniline Compounds/chemical synthesis , Indoles/chemical synthesis , Maleimides/chemical synthesis , Protein Kinase C/antagonists & inhibitors , Aniline Compounds/chemistry , Humans , Indoles/chemistry , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Maleimides/chemistry , Protein Kinase C/chemistry , Protein Kinase C beta , Structure-Activity RelationshipABSTRACT
A series of benzimidazole derivatives with the side chain on the nitrogen atom oriented to the prime site of factor Xa (FXa) were designed and synthesized. Compounds with substituted aminocarbonylmethyl groups as the side chain showed potent FXa inhibitory activity. Compounds 1 and 2 exhibited most potent inhibitory activity and were effective as anticoagulants in a DIC model.
