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.

The 5-lipoxygenase/leukotriene pathway in obesity, insulin resistance, and fatty liver disease

“…Inhibitors of LTA4H are the new kids on the block of pharmacological modulation of the 5-lipoxygenase/leukotriene pathway. DG-051, a compound targeting LTA4H, has been reported to initiate clinical trials for myocardial infarction [14]. Finally, licofelone, a dual inhibitor of COX-2 and 5-lipoxygenase with analgesic and anti-inflammatory properties and reduced gastrointestinal toxicity, has successfully completed phase III trials in patients with osteoarthritis [15].…”

Application of k-means clustering, linear discriminant analysis and multivariate linear regression for the development of a predictive QSAR model on 5-lipoxygenase inhibitors

“…The dysregulation of this enzyme causes various inflammatory diseases such as asthma, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), arthritis, psoriasis, and atherosclerosis [1][2][3]. It has been recently reported that increased production of LTs is associated with the increased risk for myocardial infarction, stroke [4] and cancer [5]. Most of the drugs that inhibit LT production are based on the suppression of the ligandreceptor interaction, inhibition of leukotriene A4 hydrolase or indirect interference in the activation of 5-LOX [6,7].…”

Targeting leukotriene B4in inflammation

“…Clinical trials for: Chronic obstructive pulmonary disease [95] bioavailability, which is now under clinical evaluation for the treatment of myocardial infarction and stroke [111]. Structurebased drug design also allowed Berlex to design a series of glutamic acid analogs as potent LTA 4 H inhibitors [112].…”