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J Med Chem. 2010 May 27;53(10):3887-98. doi: 10.1021/jm9013136.

Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.

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1
Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA.

Abstract

We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.

PMID:
20429511
PMCID:
PMC2877169
DOI:
10.1021/jm9013136
[Indexed for MEDLINE]
Free PMC Article
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