ABSTRACT
A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Piperazines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blood Proteins/chemistry , Crystallography, X-Ray , Dogs , Drug Discovery , Humans , Inflammation/drug therapy , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Weight , Piperazines/chemistry , Piperazines/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
Subject(s)
Drug Design , Drug Evaluation, Preclinical/methods , Drug Industry/methods , Models, Statistical , Toxicity Tests/methods , Animals , Discriminant Analysis , Humans , Molecular Structure , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolismABSTRACT
A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.
Subject(s)
Amides/chemical synthesis , Antirheumatic Agents/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Humans , In Vitro Techniques , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Rats , Structure-Activity Relationship , Time Factors , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.
