title: 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: Medicinal Chemistry, deCODE Chemistry, Inc., 2501 Davey Road, Woodridge, Illinois 60517, USA.
authors: Vincent
authors: V
authors: Sandanayaka
authors: Bjorn
authors: B
authors: Mamat
authors: Rama K
authors: RK
authors: Mishra
authors: Jennifer
authors: J
authors: Winger
authors: Michael
authors: M
authors: Krohn
authors: Li-Ming
authors: LM
authors: Zhou
authors: Monica
authors: M
authors: Keyvan
authors: Livia
authors: L
authors: Enache
authors: David
authors: D
authors: Sullins
authors: Emmanuel
authors: E
authors: Onua
authors: Jun
authors: J
authors: Zhang
authors: Gudrun
authors: G
authors: Halldorsdottir
authors: Heida
authors: H
authors: Sigthorsdottir
authors: Audur
authors: A
authors: Thorlaksdottir
authors: Gudmundur
authors: G
authors: Sigthorsson
authors: Margret
authors: M
authors: Thorsteinnsdottir
authors: Douglas R
authors: DR
authors: Davies
authors: Lance J
authors: LJ
authors: Stewart
authors: David E
authors: DE
authors: Zembower
authors: Thorkell
authors: T
authors: Andresson
authors: Alex S
authors: AS
authors: Kiselyov
authors: Jasbir
authors: J
authors: Singh
authors: Mark E
authors: ME
authors: Gurney
mesh_terms: D001682:Biological Availability; D002087:Butyrates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D009203:Myocardial Infarction / Q000188:drug therapy; D010446:Peptide Fragments / Q000737:chemistry; D012995:Solubility; D020521:Stroke / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D002087:Butyrates; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D008024:Ligands; D010446:Peptide Fragments; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase