ABSTRACT
A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P(1) hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P(1) moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P(1) replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.
Subject(s)
Benzimidazoles/chemistry , Chymases/antagonists & inhibitors , Protease Inhibitors/chemistry , Benzimidazoles/metabolism , Benzimidazoles/pharmacology , Binding Sites , Chymases/metabolism , Crystallography, X-Ray , Humans , Hydrophobic and Hydrophilic Interactions , Oxidation-Reduction , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Amino Acid Motifs , Anti-Inflammatory Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Crystallography, X-Ray/methods , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Subject(s)
Amides/chemistry , Benzimidazoles/chemistry , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Microsomes, Liver/metabolism , Protein-Tyrosine Kinases/chemistry , Animals , Benzimidazoles/chemical synthesis , Carboxylic Acids/chemical synthesis , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Structure-Activity RelationshipABSTRACT
A series of novel 12-membered ring macrolides was designed based on available information on structure-activity relationships and macrolide-ribosome interactions. Compounds with the desosamine and the anchor group properly attached to the 12-membered lactone ring exhibited improved activity against erythromycin-resistant organisms.
