ABSTRACT
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Models, Molecular , Pyridines/chemical synthesis , Pyridines/pharmacology , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Imidazoles/chemistry , Molecular Conformation , Molecular Structure , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Models, Biological , Pyridines/chemical synthesis , Pyridines/pharmacology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Amides/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyridines/chemistry , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.
Subject(s)
Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Drug Evaluation, Preclinical , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , 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
The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Quinazolines/chemistry , Quinazolines/pharmacology , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Conformation , Quinazolines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.
Subject(s)
IMP Dehydrogenase/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Blood Cells , Cell Proliferation/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Ketones/chemical synthesis , Ketones/pharmacology , Monocytes/drug effects , Structure-Activity Relationship , Thiones/chemical synthesis , Thiones/pharmacologyABSTRACT
The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).