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.

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.

• Authors: Vincent Sandanayaka, Bjorn Mamat, Rama K Mishra, Jennifer Winger, Michael Krohn, Li-Ming Zhou, Monica Keyvan, Livia Enache, David Sullins, Emmanuel Onua, Jun Zhang, Gudrun Halldorsdottir, Heida Sigthorsdottir, Audur Thorlaksdottir, Gudmundur Sigthorsson, Margret Thorsteinnsdottir, Douglas R Davies, Lance J Stewart, David E Zembower, Thorkell Andresson, Alex S Kiselyov, Jasbir Singh, Mark E Gurney
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 2 Pg. 573-85 (Jan 28 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 19950900 (Publication Type: Journal Article)

Chemical References

• Butyrates
• Enzyme Inhibitors
• Heterocyclic Compounds
• Ligands
• Peptide Fragments
• Epoxide Hydrolases
• leukotriene A4 hydrolase

Topics

• Biological Availability
• Butyrates (chemistry, pharmacology, therapeutic use)
• Cardiovascular Diseases (drug therapy)
• Crystallography, X-Ray
• Drug Discovery (methods)
• Enzyme Inhibitors (chemistry, therapeutic use)
• Epoxide Hydrolases (antagonists & inhibitors, biosynthesis)
• Heterocyclic Compounds (chemistry, pharmacology, therapeutic use)
• Humans
• Ligands
• Myocardial Infarction (drug therapy)
• Peptide Fragments (chemistry)
• Solubility
• Stroke (drug therapy)
• Structure-Activity Relationship