Trypanocidal Activity of 8-Methyl-5′-{[(Z)-4-Aminobut-2-enyl]-(Methylamino)}Adenosine (Genz-644131), an Adenosylmethionine Decarboxylase Inhibitor

Sleeping sickness or human African trypanosomiasis infects between 50,000 and 150,000 people each year across sub-Saharan Africa and is fatal if left untreated. Yearly estimates of people at risk are 10 million on the African continent. Current drugs for late stage disease, such as melarsoprol, have significant toxicity and resistance to melarsoprol is increasing. Another drug, eflornithine, requires 2 weeks of intravenous infusion, which is highly impractical in rural Africa (10). A promising new combination regimen for late-stage disease that appears to be effective uses eflornithine for 1 week plus oral nifurtimox for 10 days (15). This is a small-scale trial that needs to be reinforced with more data. Nevertheless, new therapies are urgently needed; because of the extreme poverty in countries with endemic disease, there has been little interest for many years within the pharmaceutical industry in discovering and developing new drugs to treat a disease that occurs primarily in developing countries (10). Polyamine metabolism of African trypanosomes has been shown to be a valid chemotherapeutic target for inhibitors aimed at critical points in the pathway such as ornithine decarboxylase (2), trypanothione synthase (11, 13), and S-adenosylmethionine decarboxylase (AdoMetDC) (6). AdoMetDC has been shown to be an essential enzyme in the trypanosome polyamine pathway, both by RNA interference knockdown (18, 19) and through the use of inhibitors, such as MDL-73811 (8), which kill parasites both in vitro (1) and in vivo (4, 6). However, while potent, MDL-73811 lacks the pharmacokinetic and tissue (central nervous system [CNS]) distribution characteristics that are essential to meet the improved target product profile for a new late-stage antitrypanosomal drug (7). We therefore started a program to synthesize analogs with high potency and better pharmacodynamic properties. Genz-644131, the 8-methyl analog of MDL-73811, was significantly more potent in vivo against trypanosomes than other analogs made at that time (5). Some adenine C-8-substituted analogs were recently tested as inhibitors of human AdoMet decarboxylase but not against the trypanosome enzyme or versus trypanosomes in vitro. (14).