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
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 fragmentbased 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) (Kd=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.
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, Jasbir,Gurney, Mark E.
experimental part
p. 573 - 585
(2010/07/09)
Development of a scalable synthetic process for DG-051B, a first-in-class inhibitior of LTA4H
DG-051B is a first-in-class small molecule inhibitor of leukotriene A4 hydrolase (LTA4H), currently in Phase II clinical development for the prevention of heart attack. Process optimization led from a linear seven-step synthetic procedure to a convergent
Enache, Livia A.,Kennedy, Isaac,Sullins, David W.,Chen, Wei,Ristic, Dragan,Stahl, Glenn L.,Dzekhtser, Sergey,Erickson, Robert A.,Yan, Changren,Muellner, Frank W.,Krohn, Michael D.,Winger, Jennifer,Sandanayaka, Vincent,Singh, Jasbir,Zembower, David E.,Kiselyov, Alex S.
supporting information; experimental part
p. 1177 - 1184
(2010/04/22)
BIARYL SUBSTITUTED HETEROCYCLE INHIBITORS OF LTA4H FOR TREATING INFLAMMATION
The present invention relates to a chemical genus of biaryl substituted heterocycle inhibitors of LTA4H (leukotriene A4 hydrolase) useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders. The compounds have general formula Ψ: An example is
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Page/Page column 29-30
(2008/06/13)
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