ABSTRACT
The indolyl-naphthyl maleimide 7 is a potent inhibitor of the classical PKC isotypes α,ß and shows excellent selectivity over the novel PKC isotypes δ,ε,η,θ and other kinases belonging to the AGC family. The SAR around 7 as well as the physico-chemical characteristics of selected derivatives and their activity in T and B cell activation and proliferation assays are discussed.
Subject(s)
B-Lymphocytes/drug effects , Maleimides/chemistry , Maleimides/pharmacology , Protein Kinase C beta/antagonists & inhibitors , Protein Kinase C-alpha/antagonists & inhibitors , T-Lymphocytes/drug effects , B-Lymphocytes/cytology , B-Lymphocytes/metabolism , Binding Sites , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Lymphocyte Activation/drug effects , Maleimides/chemical synthesis , Molecular Docking Simulation , Naphthols/chemistry , Protein Binding , Protein Kinase C beta/metabolism , Protein Kinase C-alpha/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Structure-Activity Relationship , T-Lymphocytes/cytology , T-Lymphocytes/metabolismABSTRACT
We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.
Subject(s)
Arthritis, Experimental/drug therapy , Drug Discovery , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Arthritis, Experimental/chemically induced , Collagen , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Female , Humans , Intracellular Signaling Peptides and Proteins/blood , Intracellular Signaling Peptides and Proteins/metabolism , Liver/drug effects , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/blood , Protein-Tyrosine Kinases/metabolism , Rats , Rats, Inbred Lew , Structure-Activity Relationship , Syk KinaseABSTRACT
A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing.
Subject(s)
Hypertension, Pulmonary/drug therapy , Protein Kinase Inhibitors/pharmacology , rho-Associated Kinases/antagonists & inhibitors , Animals , Crystallography, X-Ray , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Hypertension, Pulmonary/enzymology , Hypertension, Pulmonary/metabolism , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Rats , Rats, Inbred Lew , Structure-Activity Relationship , rho-Associated Kinases/metabolismABSTRACT
The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, ε, η, θ (in particular PKCε/η, and display a 10-100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCθ-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10% rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing.
Subject(s)
Naphthyridines/chemistry , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Administration, Oral , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Enterotoxins/toxicity , Interleukin-2/blood , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Mice , Naphthyridines/chemical synthesis , Naphthyridines/pharmacokinetics , Protein Kinase C/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Rats , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
Three novel aspects emerge for the reaction of [5]metacyclophane (1) with the (intermediate) phenylphosphinidene complex 2 to give the 7-phosphanorbornadiene 3. It is the first 1,4-addition of a phosphinidene complex to an unsaturated system, the first addition of a phosphinidene complex to a benzene ring, and the first [4+1] cycloaddition to an aromatic compound.
