ABSTRACT
In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Animals , Class I Phosphatidylinositol 3-Kinases , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , Enzyme Assays/methods , Humans , Mice , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , RatsABSTRACT
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
A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed and SAR studies toward activity and selectivity are described, leading to Lck inhibitors with enzymatic, cellular and in vivo potency.
