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    • 89 25 Two major categories of arginase inhibitors have been

    2023-12-20

    Two major categories of arginase inhibitors have been distinguished (Fig. 3): the first category comprises synthetic arginase inhibitors, which have been developed from the substrate l-arginine [35]; and the second category includes inhibitors derived from natural products [36]. The category of synthetic arginase inhibitors could be divided into two subgroups: the first one includes NOHA analogs; and the second one is derived from boronic 89 25 (Fig. 3a). In the l-arginine hydrolysis of arginase, the cluster of hydroxy-bridged manganese plays a crucial part (Fig. 4a) [32], because the hydrolytic process starts via nucleophilic attack by a metal-activated water molecule bridging two Mn2+ ions (Mn-cluster). This nucleophilic attack results in a tetrahedral intermediate that collapses to yield l-ornithine and urea (Fig. 4a) [32]. From the early 1990s, studies on arginase inhibition of NOHA (2) 37, 38, an intermediate product in NO biosynthesis by NOS (Fig. 1), and several Nω-hydroxyamino-α-amino acids 39, 40, resulted in the first group of substrate-derived arginase inhibitors. The inhibitors in this group such as NOHA (2) or Nω-hydroxy-nor-l-arginine (nor-NOHA, 3) (Fig. 3a) are characterized by a N-hydroxy-guanidinium side-chain, which could replace the hydroxy of the water molecule in the manganese cluster and disturb the enzymatic reaction of arginase (Fig. 4b) 40, 41. Custot et al. reported that NOHA (2) and nor-NOHA (3) were reversible and competitive inhibitors of rat liver arginase (r-ARG I) with the affinity of 3 being 20-fold higher than 2 (Ki=0.5±1 and 10±2μM, respectively) [41]. The second group of substrate-derived arginase inhibitors contains boronic acid analogs of l-arginine, first developed by Christianson and co-workers 42, 43, who were pioneers for elucidating the catalytic mechanism of arginase by the crystallographic technique [32]. This group of molecules is represented by two well-known potent arginase inhibitors: 2-(S)-amino-6-boronohexanoic acid (ABH, 4) [42] and S-(2-boronoethyl)-l-cysteine (BEC, 5) [43] (Fig. 3a). Their mechanism of arginase inhibition is based on the trigonal planar boronic acid moiety, which mimics the trigonal planar guanidinium group of l-arginine, and binds to the manganese cluster of the active site of arginase. This action results in a tetrahedral boronate complex and disturbs the enzymatic reaction (Fig. 4c) [40]. ABH (4) and BEC (5) exhibited high affinities for rat liver arginase (r-ARG I) (Ki of 0.11 and 0.4–0.6μM, respectively) 42, 43 that were similar to that of nor-NOHA (Ki=0.5μM on r-ARG I) [41]. Recently, many efforts have been aimed at improving the inhibitory potency and the ARG II/ARG I selectivity of boronic acid analogs. This approach focused on structure modification at the α-position of the carboxylic function of ABH, and resulted in a series of α,α-disubstituted boronic acid analogs (6) with the lead compound (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid [44]. This compound strongly inhibited human ARG I and II with IC50s of 223 and 509nM, respectively, and its pharmacokinetic evaluation in a male Sprague–Dawley rat model (10mg/kg, per os) showed an oral bioavailability of 28% and a Cmax of 0.45mg/l [44]. Boronic acid analogs are currently considered as the best arginase inhibitors [35]. However, this kind of compound could have a high toxicity in humans. Indeed, accidental ingestion of boric acid was responsible for the death of infants in the 1950s and 1960s 45, 46, and two boronic-acid-based drugs: a dipeptidyl peptidase inhibitor (Talabostat®) and a thrombin inhibitor (Flovagatran®), were withdrawn from the market owing to their unacceptable toxicity against human hepatocytes by DARA BioSciences and Trigen, respectively [35]. Moreover, the boronic acid group of these derivatives, which is similar to some carboxylic acids, can be removed by human liver microsomes and converted into hydroxyl or keto derivatives [35]. Therefore, chemical pharmacomodulations would be needed to enhance the selectivity of hit-compounds toward the on-target vs off-targets, to avoid undesirable side-effects and to improve the pharmacodynamic and pharmacokinetic profiles of this kind of inhibitor 46, 47, 48. Of note, nor-NOHA (3), ABH (4) and BEC (5) (Fig. 3a) are commercially available for research studies and can be used as reference inhibitors in preclinical studies searching new arginase inhibitors.