Discovery of new S-adenosylmethionine decarboxylase inhibitors for the treatment of Human African Trypanosomiasis (HAT)

Bradford Hirth; Robert H Barker Jr; Cassandra A Celatka; Jeffrey D Klinger; Hanlan Liu; Bakela Nare; Amarjit Nijjar; Margaret A Phillips; Edmund Sybertz; Erin K Willert; Yibin Xiang

doi:10.1016/j.bmcl.2009.04.096

Discovery of new S-adenosylmethionine decarboxylase inhibitors for the treatment of Human African Trypanosomiasis (HAT)

Bioorg Med Chem Lett. 2009 Jun 1;19(11):2916-9. doi: 10.1016/j.bmcl.2009.04.096. Epub 2009 Apr 24.

Authors

Bradford Hirth¹, Robert H Barker Jr, Cassandra A Celatka, Jeffrey D Klinger, Hanlan Liu, Bakela Nare, Amarjit Nijjar, Margaret A Phillips, Edmund Sybertz, Erin K Willert, Yibin Xiang

Affiliation

¹ Drug and Biomaterial R&D, Genzyme Corporation, Waltham, MA 02451, United States.

PMID: 19419862
DOI: 10.1016/j.bmcl.2009.04.096

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / chemical synthesis*
Adenosine / chemistry
Adenosine / pharmacology
Adenosylmethionine Decarboxylase / antagonists & inhibitors*
Adenosylmethionine Decarboxylase / metabolism
Animals
Blood-Brain Barrier
Drug Discovery
Humans
Mice
Trypanocidal Agents / chemical synthesis*
Trypanocidal Agents / chemistry
Trypanocidal Agents / pharmacokinetics
Trypanosoma brucei brucei / enzymology
Trypanosomiasis, African / drug therapy*

Substances

Trypanocidal Agents
Adenosylmethionine Decarboxylase
Adenosine