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Vol. 56, Issue 4, 791-796, October 1999
Institutes of Pharmaceutical Chemistry (G.E., M.H.) and Medical
Chemistry (D.S., P.C.), University of Vienna, Austria
The presence of a nitrogen atom, charged at physiological pH, has
frequently been considered to be a hallmark of P-glycoprotein (PGP)
inhibitors, although certain steroids, such as progesterone, lack a
nitrogen atom and still are active modulators of PGP. The present study
was aimed at investigating the role the nitrogen atom plays in the
activity of PGP inhibitors. Propafenone-related amines, anilines, and
amides that cover a broad range of pKa
values, as well as an ester, were synthesized and tested for multidrug resistance-reverting activity. The sum of the hydrogen bond acceptor strengths was calculated and correlated with EC50 values
for PGP inhibition. For the complete set of 12 compounds, an excellent correlation between these two parameters was found; this included the
ester GP570, which lacks a nitrogen atom but contains the strong
hydrogen bond-accepting ester unit. The interaction of the nitrogen
atom with PGP therefore is nonional and is determined by the sum of the
hydrogen acceptor strengths of the region. The high predictivity of the
obtained model is demonstrated in a leave-one-out cross-validation procedure.
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