ABSTRACT
Novel piperidine and piperazine derivatives have been designed and tested as inhibitors of LTA(4) hydrolase (LTA(4)H). Most potent compounds showed good potency in both enzymatic and functional human whole blood assay. Crystallography studies further confirmed observed structure-activity relationship and LTA(4)H binding mode for analogs from the piperidine series.
Subject(s)
Anti-Inflammatory Agents/chemistry , Enzyme Inhibitors/chemistry , Epoxide Hydrolases/antagonists & inhibitors , Piperazines/chemistry , Piperidines/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/metabolism , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Structure-Activity RelationshipABSTRACT
Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.
