Discovery of new S-adenosylmethionine decarboxylase inhibitors for the treatment of Human African Trypanosomiasis (HAT).
Modification of the structure of trypanosomal AdoMetDC inhibitor 1 (MDL73811) resulted in the identification of a new inhibitor 7a, which features a methyl substituent at the 8-position. Compound 7a exhibits improved potencies against both the trypanosomal AdoMetDC enzyme and parasites, and better blood brain barrier penetration than 1.
Drug and Biomaterial R&D, Genzyme Corporation, Waltham, MA 02451, United States.
Bradford
B
Hirth
Robert H
RH
Barker
Cassandra A
CA
Celatka
Jeffrey D
JD
Klinger
Hanlan
H
Liu
Bakela
B
Nare
Amarjit
A
Nijjar
Margaret A
MA
Phillips
Edmund
E
Sybertz
Erin K
EK
Willert
Yibin
Y
Xiang
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014346:Trypanosoma brucei brucei / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy*
D014344:Trypanocidal Agents; D012437:Adenosylmethionine Decarboxylase; D000241:Adenosine