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Antimicrobial Agents and Chemotherapy, May 2009, p. 2052-2058, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01674-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel S-Adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis{triangledown} ,{dagger}

Robert H. Barker Jr.,1* Hanlan Liu,1 Bradford Hirth,1 Cassandra A. Celatka,1 Richard Fitzpatrick,1 Yibin Xiang,1 Erin K. Willert,2 Margaret A. Phillips,2 Marcel Kaiser,3 Cyrus J. Bacchi,4,5 Aixa Rodriguez,4 Nigel Yarlett,4,6 Jeffrey D. Klinger,1 and Edmund Sybertz1

Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451,1 Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9041,2 Swiss Tropical Institute, Parasite Chemotherapy, Socinstrasse 57, P.O. Box CH-4002, Basel, Switzerland,3 Haskins Laboratory,4 Department of Biological and Health Sciences,5 Department of Chemistry and Physical Sciences, Pace University, 41 Park Row, New York, New York 100386

Received 19 December 2008/ Returned for modification 28 January 2009/ Accepted 4 March 2009

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.

* Corresponding author. Mailing address: Genzyme Corporation, 153 Second Avenue, Waltham, MA 02451. Phone: (781) 434-3425. Fax: (781) 434-3400. E-mail: Robert.barker{at}genzyme.com

{triangledown} Published ahead of print on 16 March 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, May 2009, p. 2052-2058, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01674-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bacchi, C. J., Barker, R. H. Jr., Rodriguez, A., Hirth, B., Rattendi, D., Yarlett, N., Hendrick, C. L., Sybertz, E. (2009). Trypanocidal Activity of 8-Methyl-5'-{[(Z)-4-Aminobut-2-enyl]-(Methylamino)}Adenosine (Genz-644131), an Adenosylmethionine Decarboxylase Inhibitor. Antimicrob. Agents Chemother. 53: 3269-3272 [Abstract] [Full Text]  


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