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Antimicrobial Agents and Chemotherapy, August 2009, p. 3269-3272, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.00076-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Cyrus J. Bacchi,1,2* Robert H. Barker Jr.,1,3 Aixa Rodriguez,1 Bradford Hirth,3 Donna Rattendi,1 Nigel Yarlett,1,4 Clifford L. Hendrick,3 and Edmund Sybertz3

Haskins Laboratory,1 Department of Biological and Health Sciences, Pace University, New York, New York 10038,2 Genzyme Corp., Waltham, Massachusetts 02451,3 Department of Chemistry and Physical Sciences, Pace University, New York, New York 100384

Received 20 January 2009/ Returned for modification 6 April 2009/ Accepted 11 May 2009

Genzyme 644131, 8-methyl-5'-{[(Z)-4-aminobut-2-enyl](methylamino)}adenosine, is an analog of the enzyme activated S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor and the trypanocidal agent MDL-7381, 5-{[(Z)-4-aminobut-2-enyl](methylamino)}adenosine. The analog differs from the parent in having an 8-methyl group on the purine ring that bestows favorable pharmacokinetic, biochemical, and trypanocidal activities. The compound was curative in acute Trypanosoma brucei brucei and drug-resistant Trypanosoma brucei rhodesiense model infections, with single-dose activity in the 1- to 5-mg/kg/day daily dose range for 4 days against T. brucei brucei and 25- to 50-mg/kg twice-daily dosing against T. brucei rhodesiense infections. The compound was not curative in the TREU 667 central nervous system model infection but cleared blood parasitemia and extended time to recrudescence in several groups. This study shows that AdoMetDC remains an attractive chemotherapeutic target in African trypanosomes and that chemical changes in AdoMetDC inhibitors can produce more favorable drug characteristics than the lead compound.

* Corresponding author. Mailing address: Haskins Laboratories, Pace University, 41 Park Row, New York, NY 10038. Phone: (212) 346-1246. Fax: (212) 346-1586. E-mail: cbacchi{at}pace.edu

{triangledown} Published ahead of print on 18 May 2009.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3269-3272, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.00076-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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