Discovery of 4-[(2S)-2-{[4-(4-Chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic Acid (DG-051) as a Novel Leukotriene A4 Hydrolase Inhibitor of Leukotriene B4 Biosynthesis

作者：Sandanayaka Vincent; Mamat Bjorn; Mishra Rama K; Winger Jennifer; Krohn Michael; Zhou Li Ming; Keyvan Monica; Enache Livia; Sullins David; Onua Emmanuel; Zhang Jun; Halldorsdottir Gudrun; Sigthorsdottir Heida; Thorlaksdottir Audur; Sigthorsson Gudmundur; Thorsteinnsdottir Margret; Davies Douglas R; Stewart Lance J; Zembower David E; Andresson Thorkell; Kiselyov Alex S; Singh Ja**ir; Gurney Mark E^*

来源：Journal of Medicinal Chemistry, 2010, 53(2): 573-585.

DOI：10.1021/jm900838g

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 bioavallability ( > 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.

• 出版日期2010-1-28