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.

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Sandanayaka V, Mamat B, Mishra RK, Winger J, Krohn M, Zhou LM, Keyvan M, Enache L, Sullins D, Onua E, Zhang J, Halldorsdottir G, Sigthorsdottir H, Thorlaksdottir A, Sigthorsson G, Thorsteinnsdottir M, Davies DR, Stewart LJ, Zembower DE, Andresson T, Kiselyov AS, Singh J, Gurney ME

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.

J Med Chem. 2010 Jan 28;53(2):573-85. doi: 10.1021/jm900838g.

PubMed ID

19950900 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(4-fluorophenyl)(pyridin-4-yl)methanone	Leukotriene A-4 hydrolase	IC 50 (nM)	5380000	N/A	N/A	Details
1-(4-thiophen-2-ylphenyl)methanamine	Leukotriene A-4 hydrolase	IC 50 (nM)	98	N/A	N/A	Details
1-(4-thiophen-2-ylphenyl)methanamine	Leukotriene A-4 hydrolase	Kd (nM)	98000	N/A	N/A	Details