Ornithine decarboxylase inhibitors

Eflornithine (difluoromethylornithine, DFMO) inhibits the ornithine decarboxylase of the polyamine pathway, in both the trypanosome and the mammalian cell, by acting as an irreversible competitor of the natural substrate ornithine. Inhibition of ornithine decarboxylase results in depletion of the polyamines, putrescine, spermidine and spermine, which are essential for cell proliferation. Eflornithine selectively harms the parasite and not the mammalian cells, despite acting as an ornithine decarboxylase inhibitor in both cell types. This selectivity is explained by the lower rate of ornithine decarboxylase production in the parasite, as compared to mammalian cells. Due to the high turnover rate, mammalian cells are capable of quickly replenishing inhibited ornithine decarboxylase by newly... 

Trade names Ornidyl Vaniqa (Women First) Indications Sleeping sickness, hypertrichosis Category Ornithine decarboxylase inhibitor Half-life IV 3-3.5 hours topical 8 hours... 

Bitonti, A. J., McCann, P. P., and Sjoerdsma, A. (1987). Plasmodium falciparum and Plasmodium berghei Effects of ornithine decarboxylase inhibitors on erythrocytic schizogony. Exp. Parasitol. 64, 237-243. 

Eflornithine, an ornithine decarboxylase inhibitor with antiprotozoal activity (100 mg/kg q. 6 hours), is used in the... 

Bacchi, C. J., Nathan, H. C., Clarkson, A. B., Bienen E. J., Bitonti, A. J. and McCann P. O. (1987) Effects of the ornithine decarboxylase inhibitors DL-alpha-dilluoromethylornithine and alpha-monofluroromethyldehydroornithine methyl ester alone in combination with serum against Trypanosoma brucei brucei central nervous system models. Am. J. Trop. Med. Hyg. 36 46-52. 

The dibenzyl derivative (119) of an ornithine decarboxylase inhibitor has been prepared from D glucosamine in a multistep process (sugar carbons indicated).88... 

This technique can be applied to prepare DL-a-fluoromethylputrescme (5-fluoropentane 1,4-diamine), a potent irreversible inhibitor of E colt ornithine decarboxylase, from 4-phthalimido-l -butyryl chloride, diazomethane, and hydro gen fluonde-pyridine [94 95]... 

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

Pretreatment of rats with difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, prior to exposure to a tremorigenic dose of chlordecone, also resulted in inhibition of the tremor (Tilson et al. 1986b). DFMO was more effective if given 5 hours prior to the chlordecone than if given 24 hours prior to exposure. The DFMO was ineffective if given 19 hours after chlordecone exposure. These results suggest an interaction of the polyamine synthetic pathway with tremors produced by chlordecone. The mechanism of the interaction is unclear but may involve effects of polyamines on intracellular calcium homeostasis. Persons being treated with DFMO for cancer or protozoal infections would be likely to have reduced tremor severity after exposure to chlordecone. 

Aminooxy compounds can be viewed as O-ethers of HA and are discussed here in terms of their potential anticancer activity. Thus, l-aminooxy-3-aminopropane (APA) is a potent reversible inhibitor of mammalian ornithine decarboxylase (ODC) and of S-adenosylmethionine decarboxylase (SAMDC) , and 6 -(5 -deoxy-5 -adenosyl)methylsul-fonium 0-ethylhydroxylamine (AMA) was reported to be an efficient reversible inhibitor of the latter enzyme . 

Ornithine decarboxylase catalyzes the conversion of ornithine into putrescine. Like other polyamines, the latter is involved in the regulation of cell development. Inhibition of this enzyme has been an important goal in medicinal chemistry. In this context, difluoroornithine has been shown to be an excellent inhibitor... 

Metabolism of polyamines has a direct action on cell proliferation. Thus, it is a therapeutic target for the design of antitumor agents. However, inhibition of ornithine decarboxylase (ODC) by specific inhibitors does not completely cancel the activity. This is due to the existence of other biosynthetic pathways (i.e., SAM-DC). These pathways are themselves regulated by polyamines. 

S.2.3.3 Treatment of Trypanosomiasis The difluoromethylornithine (DFMO), eflomithine is a mechanism-based inhibitor of ornithine decarboxylase— a pyridoxal-dependent key enzyme of the polyamine s biosynthesis from ornithine. Fluorine atoms are essential for the inhibition process (cf. Chapter 7). Eflornithine was first clinically developed for cancer, but its development has been abandoned for this indication. The activity of eflornithine on trypanosomes was then discovered. Now, despite its very low bioavailability, eflornithine is the best therapy for sleeeping sickness (trypanosomiasis)—in particular, at the cerebral stage—due to Trypanosoma brucei gambiense parasite. Eflornithine is registered with orphan drug status and is distributed by the WHO. 

It is an inhibitor of ornithine decarboxylase and is used as second line therapy for advanced CNS African trypanosomiasis. After oral or IV administration, peak plasma level is reached rapidly and elimination half life is approximately three hours. 

Bowlin, T. L., Davis, G. F., and McKown, B. J. (1988). Inhibition of alloantigen-induced cytolytic T lymphocytes in vitro with (2R, 5R)-6-heptyne-2, 5-diamine, an irreversible inhibitor of ornithine decarboxylase. Cell. Immunol. Ill, 443-450. 

Eflornithine (Vaniqa) is an irreversible inhibitor of ornithine decarboxylase, which catalyzes the rate-limiting step in the biosynthesis of polyamines. Polyamines are required for cell division and differentiation, and inhibition of ornithine decarboxylase affects the rate of hair growth. Topical eflornithine has been shown to be effective in reducing facial hair growth in approximately 30% of women when applied twice daily for 6 months of therapy. Hair growth was observed to return to pretreatment levels 8 weeks after discontinuation. Local adverse effects include stinging, burning, and folliculitis. 

Polyamines such as spermine and spermidine, involved in DNA packaging, are derived from methionine and ornithine by the pathway shown in Figure 22-30. The first step is decarboxylation of ornithine, a precursor of arginine (Fig. 22-10). Ornithine decarboxylase, a PLP-requiring enzyme, is the target of several powerful inhibitors used as pharmaceutical agents (Box 22-2). ... 

In mammalian cells, ornithine decarboxylase undergoes rapid turnover—that is, a constant round of enzyme degradation and synthesis. In some trypanosomes, however, the enzyme—for reasons not well understood—is stable, not readily replaced by newly synthesized enzyme. An inhibitor of ornithine decarboxylase that binds permanently to the enzyme would thus have little effect on human cells, which could rapidly replace inactivated enzyme, but would adversely affect the parasite. 

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