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Novel S-Adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis

  • Barker, Robert H. Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451
  • Liu, Hanlan Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451
  • Hirth, Bradford Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451
  • Celatka, Cassandra A. Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451
  • Fitzpatrick, Richard Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451
  • Xiang, Yibin Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451
  • Willert, Erin K. Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9041
  • Phillips, Margaret A. Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9041
  • Kaiser, Marcel Swiss Tropical Institute, Parasite Chemotherapy, Socinstrasse 57, P.O. Box CH-4002, Basel, Switzerland
  • Bacchi, Cyrus J. Department of Biological and Health Sciences
  • Rodriguez, Aixa Haskins Laboratory
  • Yarlett, Nigel Department of Chemistry and Physical Sciences, Pace University, 41 Park Row, New York, New York 10038
  • Klinger, Jeffrey D. Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451
  • Sybertz, Edmund Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451
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  • Antimicrobial Agents and Chemotherapy. - American Society for Microbiology. - 2009, vol. 53, no. 5, p. 2052-2058
Pharmacology (medical)
Pharmacology
Infectious Diseases
English 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.
Language
  • English
Open access status
bronze
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https://sonar.ch/global/documents/174151
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