ABSTRACT
Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.
Subject(s)
Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Administration, Oral , Animals , Benzoxazines/chemistry , Combinatorial Chemistry Techniques , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Male , Molecular Structure , Pyrazoles/chemistry , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed.
Subject(s)
Enzyme Inhibitors/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Mitogen-Activated Protein Kinase 8/antagonists & inhibitors , Mitogen-Activated Protein Kinase 9/antagonists & inhibitors , Models, Chemical , Structure-Activity RelationshipABSTRACT
The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.
Subject(s)
Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Indoles/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Molecular Weight , Oxazoles/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Biological Transport, Active/drug effects , Caco-2 Cells , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , In Vitro Techniques , Indoles/chemistry , Leukocytes, Mononuclear/drug effects , Molecular Structure , Molecular Weight , Structure-Activity RelationshipABSTRACT
This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Purines/chemical synthesis , Purines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacologyABSTRACT
A versatile route for the synthesis of homochiral alpha-ketoamide analogues of amino acids is described. Incorporation of this functionality into peptide sequences using either solution or solid-phase chemistry resulted in potent inhibitors of the Hepatitis C Virus NS3 proteinase.