Novel S-adenosylmethionine decarboxylase inhibitors for the treatment of human African trypanosomiasis

Robert H. Barker, Hanlan Liu, Bradford Hirth, Cassandra A. Celatka, Richard Fitzpatrick, Yibin Xiang, Erin K. Willert, Margaret A. Phillips, Marcel Kaiser, Cyrus J. Bacchi, Aixa Rodriguez, Nigel Yarlett, Jeffrey D. Klinger, Edmund Sybertz

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Trypanosomiasis remains a significant disease across the sub-Saharan African continent, with 50,000 to 70,000 individuals infected. The utility of current therapies is limited by issues of toxicity and the need to administer compounds intravenously. We have begun a program to pursue lead optimization around MDL 73811, an irreversible inhibitor of S-adenosylmethionine decarboxylase (AdoMetDC). This compound is potent but in previous studies cleared rapidly from the blood of rats (T. L. Byers, T. L. Bush, P. P. McCann, and A. J. Bitonti, Biochem. J. 274:527-533). One of the analogs synthesized (Genz-644131) was shown to be highly active against Trypanosoma brucei rhodesiense in vitro (50% inhibitory concentration, 400 pg/ml). Enzyme kinetic studies showed Genz-644131 to be approximately fivefold more potent than MDL 73811 against the T. brucei brucei AdoMetDC-prozyme complex. This compound was stable in vitro in rat and human liver microsomal and hepatocyte assays, was stable in rat whole-blood assays, did not significantly inhibit human cytochrome P450 enzymes, had no measurable efflux in CaCo-2 cells, and was only 41% bound by serum proteins. Pharmacokinetic studies of mice following intraperitoneal dosing showed that the half-life of Genz-644131 was threefold greater than that of MDL 73811 (7.4 h versus 2.5 h). Furthermore, brain penetration of Genz-644131 was 4.3-fold higher than that of MDL 73811. Finally, in vivo efficacy studies of T. b. brucei strain STIB 795-infected mice showed that Genz-644131 significantly extended survival (from 6.75 days for controls to >30 days for treated animals) and cured animals infected with T. b. brucei strain LAB 110 EATRO. Taken together, the data strengthen validation of AdoMetDC as an important parasite target, and these studies have shown that analogs of MDL 73811 can be synthesized with improved potency and brain penetration.

Original languageEnglish (US)
Pages (from-to)2052-2058
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume53
Issue number5
DOIs
StatePublished - May 2009

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Adenosylmethionine Decarboxylase
African Trypanosomiasis
Cytochrome P-450 Enzyme System
Trypanosoma brucei rhodesiense
Trypanosoma brucei brucei
Caco-2 Cells
Trypanosomiasis
Brain
Inhibitory Concentration 50
Half-Life
Blood Proteins
Hepatocytes
Parasites
Pharmacokinetics
8-methyl-5'-((4-aminobut-2-enyl)(methylamino))adenosine
MDL 73811
Survival
Liver
Enzymes

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Barker, R. H., Liu, H., Hirth, B., Celatka, C. A., Fitzpatrick, R., Xiang, Y., ... Sybertz, E. (2009). Novel S-adenosylmethionine decarboxylase inhibitors for the treatment of human African trypanosomiasis. Antimicrobial Agents and Chemotherapy, 53(5), 2052-2058. https://doi.org/10.1128/AAC.01674-08

Novel S-adenosylmethionine decarboxylase inhibitors for the treatment of human African trypanosomiasis. / Barker, Robert H.; Liu, Hanlan; Hirth, Bradford; Celatka, Cassandra A.; Fitzpatrick, Richard; Xiang, Yibin; Willert, Erin K.; Phillips, Margaret A.; Kaiser, Marcel; Bacchi, Cyrus J.; Rodriguez, Aixa; Yarlett, Nigel; Klinger, Jeffrey D.; Sybertz, Edmund.

In: Antimicrobial Agents and Chemotherapy, Vol. 53, No. 5, 05.2009, p. 2052-2058.

Research output: Contribution to journalArticle

Barker, RH, Liu, H, Hirth, B, Celatka, CA, Fitzpatrick, R, Xiang, Y, Willert, EK, Phillips, MA, Kaiser, M, Bacchi, CJ, Rodriguez, A, Yarlett, N, Klinger, JD & Sybertz, E 2009, 'Novel S-adenosylmethionine decarboxylase inhibitors for the treatment of human African trypanosomiasis', Antimicrobial Agents and Chemotherapy, vol. 53, no. 5, pp. 2052-2058. https://doi.org/10.1128/AAC.01674-08
Barker, Robert H. ; Liu, Hanlan ; Hirth, Bradford ; Celatka, Cassandra A. ; Fitzpatrick, Richard ; Xiang, Yibin ; Willert, Erin K. ; Phillips, Margaret A. ; Kaiser, Marcel ; Bacchi, Cyrus J. ; Rodriguez, Aixa ; Yarlett, Nigel ; Klinger, Jeffrey D. ; Sybertz, Edmund. / Novel S-adenosylmethionine decarboxylase inhibitors for the treatment of human African trypanosomiasis. In: Antimicrobial Agents and Chemotherapy. 2009 ; Vol. 53, No. 5. pp. 2052-2058.
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