Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA₄H) 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 LTA₄H. Ligand efficiency was followed throughout our structure−activity studies. As applied within the context of LTA₄H 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.