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
We describe two series of Syk inhibitors which potently abrogate Syk kinase function in enzymatic assays, cellular assays and in primary cells in the presence of blood. Introduction of a 7-aminoindole substituent led to derivatives with good kinase selectivity and little or no hERG channel inhibition (3b, 10c).
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/blood , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/blood , Humans , Indoles/blood , Indoles/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/chemistry , Syk KinaseABSTRACT
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
A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.
Subject(s)
Aminopyridines/chemical synthesis , Naphthyridines/chemical synthesis , Protein Kinase C/antagonists & inhibitors , Active Transport, Cell Nucleus , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Cardiomegaly/drug therapy , Cardiomegaly/pathology , Cell Nucleus/metabolism , Histone Deacetylases/metabolism , Isoenzymes/antagonists & inhibitors , Male , Models, Molecular , Muscle Cells/drug effects , Muscle Cells/metabolism , Muscle Cells/pathology , Myocardium/metabolism , Myocardium/pathology , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Phosphorylation , Protein Binding , Rats , Rats, Inbred Dahl , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.
Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Aminopyridines/chemical synthesis , Naphthyridines/chemical synthesis , Piperazines/chemical synthesis , Protein Kinase C/antagonists & inhibitors , 2,2'-Dipyridyl/chemical synthesis , 2,2'-Dipyridyl/pharmacokinetics , 2,2'-Dipyridyl/pharmacology , Active Transport, Cell Nucleus , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Cardiomegaly/drug therapy , Cardiomegaly/enzymology , Cardiomegaly/pathology , Cell Nucleus/metabolism , Histone Deacetylases/metabolism , Isoenzymes/antagonists & inhibitors , Male , Models, Molecular , Muscle Cells/drug effects , Muscle Cells/metabolism , Muscle Cells/pathology , Myocardium/metabolism , Myocardium/pathology , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Phosphorylation , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Rats , Rats, Inbred Dahl , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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.
