Aromatic replacements for cyclohexane moiety

Published by MatTodd on 12 September 2010 - 12:47pm


(2-benzoyl-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one)
InChI=1S/C19H18N2O2/c22-18-13-20(19(23)15-7-2-1-3-8-15)12-17-16-9-5-4-6-14(16)10-11-21(17)18/h1-9,17H,10-13H2
SMILES O=C1CN(C(C2=CC=CC=C2)=O)CC3N1CCC4=C3C=CC=C4
The analog containing benzoyl in place of cyclohexanoyl was described in one of the early PZQ patents. Interestingly the patent says this (column 2, top): "[The enantiopure compound] exhibits its althelmintic activity on [organism] in a dose which is up to five times smaller than that of the racemic [compound]. This effect could not be expected, since one would anticipate a doubling of the efficiency at most, if only one isomer were active."

Comments

kilomentor's picture

It is only when looking at two enantiomer drug candidates most simply that one thinks that the increase in activity one would get would be a factor of two. Even if, as in the case of Praziquanamine, where the bad enantiomer is inactive, this wrong handed compound can influence the amount of good drug that reaches the biological target. This wrong prazaquanamine is not unreactive in the body. It will still be metabolized and there is a good chance that it will tie up the same catabolizing enzymes that Praziquanamine uses and enhance the amount of drug delivered to the biological target. The fact that the wrong enantiomer has a strong taste while POraiquanamine does not, shows that at least for the sensing molecules on the tongue, the bad Praziquanamine binds more strongly.
This idea that if the non-drug enantiomer was inactive the drug enantiomer would show double the activity is a mild misconception that I certainly held for a long time.