ABSTRACT
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Autoimmune Diseases/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Immunity/drug effects , Janus Kinase 2/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacologyABSTRACT
A series of C-2, C-8, and N-9 trisubstituted purine based inhibitors of TNF-alpha production are described. The most potent analogs showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell based assay. The SAR of the series was optimized with the aid of X-ray co-crystal structures of these inhibitors bound with mutated p38 (mp38).
Subject(s)
Purines/chemistry , Tumor Necrosis Factor-alpha/chemistry , Cell Line , Chemistry, Pharmaceutical , Crystallography, X-Ray , Drug Design , Humans , Lipopolysaccharides/chemistry , Models, Chemical , Models, Molecular , p38 Mitogen-Activated Protein Kinases/chemistry , p38 Mitogen-Activated Protein Kinases/geneticsABSTRACT
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Subject(s)
Arthritis, Experimental/drug therapy , Osteoarthritis/drug therapy , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/classification , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/chemically induced , Binding Sites , Crystallography, X-Ray , Disease Models, Animal , Drug Evaluation, Preclinical , Hydrogen Bonding , Iodoacetates , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Structure , Osteoarthritis/chemically induced , Phenylurea Compounds/classification , Pyrimidines/classification , Rats , Stereoisomerism , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Subject(s)
Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Binding Sites , Crystallography, X-Ray , Hydrogen Bonding , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Structure , Phenylurea Compounds/classification , Pyrimidines/classification , Stereoisomerism , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
Subject(s)
Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Pyrazolones/chemical synthesis , Pyrazolones/pharmacology , Animals , Disease Models, Animal , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Kinetics , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Conformation , Osteoarthritis/prevention & control , Pyrazolones/chemistry , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-alpha production.
Subject(s)
Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Pyrimidines/chemical synthesis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Acetaldehyde , Binding Sites , Cell Line , Humans , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Structure , Protein Conformation , Pyrimidines/pharmacology , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.
Subject(s)
Pyrazolones/chemistry , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Lipopolysaccharides/pharmacology , Models, Molecular , Pyrazolones/administration & dosage , Pyrazolones/pharmacokinetics , Pyrazolones/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.
