ABSTRACT
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.
Subject(s)
Butyrates/pharmacology , Cardiovascular Diseases/drug therapy , Drug Discovery/methods , Epoxide Hydrolases/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Biological Availability , Butyrates/chemistry , Butyrates/therapeutic use , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Epoxide Hydrolases/biosynthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/therapeutic use , Humans , Ligands , Myocardial Infarction/drug therapy , Peptide Fragments/chemistry , Solubility , Stroke/drug therapy , Structure-Activity RelationshipABSTRACT
The same two major CYP mediated metabolites of DG-051 were produced in the presence of rat, dog, monkey and human liver microsomes. Their respective structures were hypothesized based on mass spectrometry data correlated with the parent structure and confirmed by comparison with authentic synthetic samples. The number of regioisomers synthesized as candidates for metabolite M1 was narrowed down using a metabolic study of a selectively deuterated DG-051 analogue.