Zwitterionic Sulfobetaine Inhibitors of Squalene Synthase.
A substantial number of sulfobetaines (e.g., 10) have been synthesized and evaluated as inhibitors of squalene synthase (SS) on the basis of the idea that their zwitterionic structure would have properties conducive both to binding in the active site and to passage through cell membranes. When the simple sulfobetaine moiety is incorporated into compounds containing hydrophobic portions like those in farnesyl diphosphate (1) or presqualene diphosphate (2), inhibition of SS in a rat liver microsomal assay was indeed observed. For example, farnesylated sulfobetaine 10 has IC(50) = 10 &mgr;M and aromatic derivative 35 has IC(50) = 2 &mgr;M for SS inhibition. A wide variety of structural modifications, exemplified by compounds 43, 52, 76, 85, 91, 99, 111, and 115, was investigated. Unfortunately, no inhibitors in the submicromolar range were discovered, and exploration of a different type of zwitterion seems necessary if this appealing approach to inhibition of SS is going to provide a potential antihypercholesterolemic agent.
Spencer
Thomas A.
TA
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, and Department of Biochemistry and Molecular Biology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799.
Onofrey
Thomas J.
TJ
Cann
Reginald O.
RO
Russel
Jonathon S.
JS
Lee
Laura E.
LE
Blanchard
Daniel E.
DE
Castro
Alfredo
A
Gu
Peide
P
Jiang
Guojian
G
Shechter
Ishaiahu
I