Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury

Abstract

Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.

Crystal structures ofLeishmania mexicanaarginase complexed with α,α-disubstituted boronic amino-acid inhibitors

“…In comparison with the parent inhibitor ABH, the α, α-disubstituted boronic acid amino acids ABH PE and ABH DP exhibit modestly improved affinity for S. mansoni arginase (5.0-fold and 2.4-fold, respectively) (Hai et al, 2014), modestly improved inhibitory potency (IC 50 ) against human arginase I (6.5-fold and 7.4-fold, respectively) (Van Zandt et al, 2013), and modestly improved inhibitory potency against human arginase II (3.8-fold and 7.4-fold, respectively) (Golebiowski et al, 2013). However, neither ABH PE nor ABH DP exhibit improved inhibitory potency against LmARG (Table 2, Figure 2).…”

“…The binding mode of ABH PE in SmARG is unique, since only this particular enzyme has a groove that accommodates the piperidine ring of ABH PE (Figure 5). Notably, the piperidine ring of ABH PE does not interact directly with active site residues in human arginases I and II, although a water-mediated interaction is observed in the human arginase I-ABH PE complex (Van Zandt et al, 2013). …”

“…To expand the chemical space of arginase inhibitor design, novel α,α-disubstituted boronic acid inhibitors based on ABH have been developed and evaluated against human arginase I, human arginase II, Plasmodium falciparum arginase, and Schistosoma mansoni arginase (Ilies et al, 2011; Golebiowski et al, 2013; Van Zandt et al ., 2013; Hai et al, 2014). While the l -boronic acid side chain of these inhibitors binds in the active site cleft in identical fashion to that of the parent compound ABH, the additional d -side chain of these inhibitors can make new interactions in the outer rim of the active site.…”

“…Here, we report the crystal structures of LmARG with the α,α-disubstituted boronic acid inhibitors ( R )-2-amino-6-borono-2-[2-(piperidin-1-yl)ethyl]hexanoic acid (ABH PE ) and ( R )-2-amino-6-borono-2-[1-(3,4-dichlorobenzyl)piperidin-4-yl]hexanoic acid (ABH DP ) (Figure 1c) (Golebiowski et al, 2013; Van Zandt et al ., 2013). Structural comparisons with human and parasitic arginase complexes reveal interesting differences in the binding modes of the d -side chains of these inhibitors.…”

Big opportunities for small molecules in immuno-oncology

“…The most effective compounds have half-maximal inhibitory concentration values of ~0.5 μM against both ARG1 and ARG2 and moderate bioavailability 39 . Also present at high levels in MDSCs is iNOS, which converts arginine to nitric oxide.…”