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 (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.
Sandanayaka
Vincent
V
Medicinal Chemistry, deCODE Chemistry, Inc., 2501 Davey Road, Woodridge, Illinois 60517, USA.
Mamat
Bjorn
B
Mishra
Rama K
RK
Winger
Jennifer
J
Krohn
Michael
M
Zhou
Li-Ming
LM
Keyvan
Monica
M
Enache
Livia
L
Sullins
David
D
Onua
Emmanuel
E
Zhang
Jun
J
Halldorsdottir
Gudrun
G
Sigthorsdottir
Heida
H
Thorlaksdottir
Audur
A
Sigthorsson
Gudmundur
G
Thorsteinnsdottir
Margret
M
Davies
Douglas R
DR
Stewart
Lance J
LJ
Zembower
David E
DE
Andresson
Thorkell
T
Kiselyov
Alex S
AS
Singh
Jasbir
J
Gurney
Mark E
ME
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
D002087:Butyrates; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D008024:Ligands; D010446:Peptide Fragments; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase