title: Trypanocidal activity of 8-methyl-5'-{[(Z)-4-aminobut-2-enyl]-(methylamino)}adenosine (Genz-644131), an adenosylmethionine decarboxylase inhibitor.
abstract: 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.
authors.affiliation: Haskins Laboratories, Pace University, 41 Park Row, New York, NY 10038, USA. cbacchi@pace.edu
authors.forename: Cyrus J
authors.initials: CJ
authors.lastname: Bacchi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Barker
authors.forename: Aixa
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Bradford
authors.initials: B
authors.lastname: Hirth
authors.forename: Donna
authors.initials: D
authors.lastname: Rattendi
authors.forename: Nigel
authors.initials: N
authors.lastname: Yarlett
authors.forename: Clifford L
authors.initials: CL
authors.lastname: Hendrick
authors.forename: Edmund
authors.initials: E
authors.lastname: Sybertz
mesh_terms: 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
chemical_list: C544300:8-methyl-5'-((4-aminobut-2-enyl)(methylamino))adenosine; D014344:Trypanocidal Agents; D012437:Adenosylmethionine Decarboxylase; D000241:Adenosine