Macrocyclic piperazinones as potent dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I

Christopher J Dinsmore; C Blair Zartman; Jeffrey M Bergman; Marc T Abrams; Carolyn A Buser; J Christopher Culberson; Joseph P Davide; Michelle Ellis-Hutchings; Christine Fernandes; Samuel L Graham; George D Hartman; Hans E Huber; Robert B Lobell; Scott D Mosser; Ronald G Robinson; Theresa M Williams

doi:10.1016/j.bmcl.2003.11.051

Macrocyclic piperazinones as potent dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I

Bioorg Med Chem Lett. 2004 Feb 9;14(3):639-43. doi: 10.1016/j.bmcl.2003.11.051.

Authors

Christopher J Dinsmore¹, C Blair Zartman, Jeffrey M Bergman, Marc T Abrams, Carolyn A Buser, J Christopher Culberson, Joseph P Davide, Michelle Ellis-Hutchings, Christine Fernandes, Samuel L Graham, George D Hartman, Hans E Huber, Robert B Lobell, Scott D Mosser, Ronald G Robinson, Theresa M Williams

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. [email protected]

PMID: 14741259
DOI: 10.1016/j.bmcl.2003.11.051

Abstract

A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed.

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Humans
Inhibitory Concentration 50
Molecular Structure
Piperazines / chemistry
Piperazines / pharmacology*
Protein Prenylation
Structure-Activity Relationship
Tumor Cells, Cultured / drug effects*
Tumor Cells, Cultured / enzymology

Substances

Enzyme Inhibitors
Heterocyclic Compounds
Piperazines
Alkyl and Aryl Transferases
geranylgeranyltransferase type-I
p21(ras) farnesyl-protein transferase