Trypanocidal activity of 8-methyl-5'-{[(Z)-4-aminobut-2-enyl]-(methylamino)}adenosine (Genz-644131), an adenosylmethionine decarboxylase inhibitor.
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.
Bacchi
Cyrus J
CJ
Haskins Laboratories, Pace University, 41 Park Row, New York, NY 10038, USA. cbacchi@pace.edu
Barker
Robert H
RH
Rodriguez
Aixa
A
Hirth
Bradford
B
Rattendi
Donna
D
Yarlett
Nigel
N
Hendrick
Clifford L
CL
Sybertz
Edmund
E
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D004285:Dogs; D011897:Random Allocation; D051381:Rats; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000472:pathogenicity; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000472:pathogenicity; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000382:microbiology
C544300:8-methyl-5'-((4-aminobut-2-enyl)(methylamino))adenosine; D014344:Trypanocidal Agents; D012437:Adenosylmethionine Decarboxylase; D000241:Adenosine