Compositions and methods for inhibiting arginase activity

Details Compositions and methods for inhibiting arginase activity Compositions and methods for inhibiting arginase activity

2000-04-10

2002-05-14

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Boron containing doai

C562S007000

Reexamination Certificate

active

06387890

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates generally to enzyme inhibitors, more particularly to inhibitors of the enzyme designated arginase.
Each individual excretes roughly ten kilograms of urea per year, as a result of the hydrolysis of arginine in the final cytosolic step of the urea cycle (Krebs et al., 1932, Hoppe-Seyler's Z. Physiol. Chem. 210:33-66). The activity of the liver enzyme, arginase, permits disposal of nitrogenous wastes which result from protein catabolism (Herzfeld et al., 1976, Biochem. J. 153:469-478). In tissues which lack a complete complement of the enzymes which catalyze the reactions of the urea cycle, arginase regulates cellular concentrations of arginine and ornithine, which are used for biosynthetic reactions (Yip et al., 1972, Biochem. J. 127:893-899). Arginine is used, by way of example, in the synthesis of nitric oxide. In macrophages, arginase activity is reciprocally coordinated with the activity of the enzyme, nitric oxide synthase. Reciprocal coordination of the activities of arginage and nitric oxide (NO) gynthage modulates NO-dependent cytotoxicity (Corraliza et al., 1995, Biochem. Biophys. Res. Commun. 206:667-673; Daghigh et al., 1994, Biochem. Biophys. Res. Commun. 202:174-180; Chénais et al., 1993, Biochem. Biophys. Res. Commun. 196:1558-1565; Klatt et al., 1993, J. Biol. Chem. 268:14781-14787; Keller et al., 1991, Cell. Immunol. 134:249-256; Albina et al., 1995, J. Immunol. 155:4391-4396).
Synthesis and evaluation of non-reactive arginine analogs for use as enzyme inhibitors or receptor antagonists is a rapidly growing area of medicinal chemical research (Griffith et al., 1995, Annu. Rev. Physiol. 57:707-736; Gross et al., 1990, Biochem. Biophys. Res. Commun. 170:96-103; Hibbs et al., 1987, J. Immunol. 138:550-565; Lambert et al., 1991, Life Sci. 49:69-79; Olken et al., 1992, J. Med. Chem. 35:1137-1144; Feldman et al., 1993, J. Med. Chem. 36:491-496; Narayanan et al., 1994, FASEB J. 8:A360; Narayanan et al., 1994, J. Med. Chem. 37:885-887; Moore et al., 1994, J. Med. Chem. 37:3886-3888; Moynihan et al., 1994, J. Chem. Soc. Perkin Trans.769-771; Robertson et al., 1995, J. Bioorganic Chem. 23:144-151).
To date, the X-ray crystal structure of one of the enzymes of mammalian arginine catabolism, namely rat liver arginase, is available (Kanyo et al., 1996, Nature 383:554-557). Rat liver arginase is a trimeric metalloenzyme which contains a bi-nuclear manganese cluster in the active site of each subunit. This bi-nuclear cluster is required for maximal catalytic activity (Reczkowski et al., 1992, J. Am. Chem. Soc. 114:10992-10994).
As noted herein, arginase catalyzes divalent cation-dependent hydrolysis of L-arginine to form L-ornithine and urea. The enzyme is currently known to serve three important functions: production of urea, production of ornithine, and regulation of substrate arginine levels for nitric oxide synthase (Jenkinson et al., 1996, Comp. Biochem. Physiol. 114B:107-132; Kanyo et al., 1996, Nature 383:554-557; Christianson, 1997, Prog. Biophys. Molec. biol. 67:217-252). Urea production provides a mechanism to excrete nitrogen in the form of a highly soluble, non-toxic compound, thus avoiding the potentially dangerous consequences of high ammonia levels. L-ornithine is a precursor for the biosynthesis of polyamines, spermine, and spermidine, which have important roles in cell proliferation and differentiation. Finally, arginase modulates production of nitric oxide by regulating the levels of arginine present within tissues.
Since both NO synthase and arginase compete for the same substrate, the possibility of reciprocal regulation of both arginine metabolic pathways has recently been explored (Modelell et al., 1995, Eur. J. Immunol. 25:1101-1104; Wang et al., 1995, Biochem. Biophys. Res. Commun. 210:1009-1016). Furthermore, N
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-hydroxy-L-arginine (L-HO-Arg), an intermediate in the NO synthase reaction (Pufahl et al., 1992, Biochemistry 31:6822-6828; Klau et al, 1993, J. Biol. Chem. 268:14781-14787; Furchgom, 1995, Annu. Rev. Pharmacol. Toxicol., 35:1-27; Yamaguchi et al., 1992, Fur. J. Biochem., 204:547-552; Pufahl et al., 1995, Biochemisty 34:1930-1941), is an endogenous arginase inhibitor (Chenais et al., 1993, Biochem. Biophys. Res. Commun., 196:1558-1565; Buga et al., 1996, Am. J. Physiol. Heart Circ. Physiol. 271:H1988-H1998 Daghigh et al., 1994, Biochem. Biophys. Res. Commun, 202;174-180; Boucher et al., 1994, Biochem. Biophys. Res. Commun. 203:1614-1621). The phenomenon of reciprocal regulation between arginase and NO synthase has only recently been examined (Chakder and Rattan, 1997, J. Pharmacol. Exp. Ther. 282:378-384; Langle et al., 1997, Transplantation 63:1225-1233; Langle et al., 1995, Transplantation 59:1542-1549). In the internal anal sphincter (IAS), it was shown that exogenous administration of arginase attenuates NO synthase-mediated non-adrenergic and non-cholinergic (NANC) nerve-mediated relaxation (Chakder and Rattan, 1997, J. Pharmacol. Exp. Ther. 282:378-384).
An excess of arginase has recently been associated with a number of pathological conditions that include gastric cancer (Wu et al., 1992, Life Sci. 51:1355-1361; Leu and Wang, 1992, Cancer 70:733-736; Straus et al., 1992, Clin. Chim. Acta 210:5-12; Ikemoto et al, 1993, Clin. Chem. 39:794-799; Wu et al., 1994, Dig. Dis. Sci. 39:1107-1112), certain forms of liver injury (Ikemoto et al., 1993, Clin. Chem. 39:794-799), and pulmonary hypertension following the orthotopic liver transplantation (Langle et al., 1997, Transplantation 63:1225-1233; Langle et al., 1995, Transplantation 59:1542-1549). Furthermore, high levels of arginase can cause impairment in NANC-mediated relaxation of the IAS (Chakder and Rattan, 1997, J. Pharmacol. Esp. Ther. 282:378-384). Previous studies have demonstrated that arginase pre-treatment causes significant suppression of the NANC nerve-mediated relaxation of the IAS (Chakder and Rattan 1997, J. Pharmacol. Exp. Ther. 282:378-384) that is mediated primarily via the L-arginine-NO synthase pathway (Rattan and Chakder, 1992, Am. J. Physiol. Gastrointest. Liver Physiol. 262: G107-G112; Rattan and Chakder, 1992, Gastroenterology 103:43-50). Impairment in NANC relaxation by excess arginase may be related to L-arginine depletion (Wang et al., 1995, Eur. J. Immunol. 25:1101-1104). Furthermore, suppressed relaxation could be restored by the arginase inhibitor L-HO-Arg. It is possible, therefore, that patients with certain conditions associated with an increase in arginase activity may stand to benefit from treatment with arginase inhibitors. However, an arginase inhibitor such as L-OH-Arg can not be selective since it also serves as a NO synthase substrate (Pufahl et al., 1992, Biochemistry 31:6822-6828; Furchgott, 1995, Annu. Rev. Pharmacol. Toxicol. 25:1-27; Pufahl et al, 1995, Biochemistry 34:1930-1941; Chemais et al., 1993, Biochem. Biophys. Res. Commun. 196:1558-1565; Boucher et al., 1994, Biochem. Biophys. Res. Commun. 203:1614-1621; Griffith and Stuehr, 1995, Annu. Rev. Physiol. 57:707-736). Because of this, the exact role of arginase in pathophysiology and the potential therapeutic actions of arginase inhibitors remains undetermined.
Erectile dysfunction afflicts one-half of the male population over the age of forty. This malady often results from defects in the complex cascade of enzyme-catalyzed reactions governing blood flow into and out of the corpus cavemosum, a chamber of muscular, spongy tissue that becomes engorged with blood in the erect penis. Defects that compromise cavemosal blood flow often occur as secondary complications related to other health conditions, such as heart disease, hypertension, diabetes, use of certain medications, and the like.
A need remains for inhibitors of arginase activity, which are useful for treating diseases or disorders characterized either by abnormally high arginase activity in a tissue of a mammal or by abnormally low nitric oxide synthase activity in a tissue of the mammal.
SUMMARY OF THE INVENTION
The invention include a composition comprising an arginase inhibi

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