Scheme 3 . Structure and SS values of
rasagiline and the derivatives selected for the next stage of the
investigation.
To verify if any molecule in the selected subset considerably diverges
(in any of its properties) from the average value of the reference
set,140-142 four exclusion scores
(SE) were also evaluated (SE,ADME2,
SE,ADME8, SE,ADMET and
SE,ADMETSA). Their equations can be found in Appendix
S2 of Supporting Information. SE,ADME2 is the same to
that formerly reported,162 and the others use the same
kind of scrutiny but including 8 terms for ADME properties, two terms
related to toxicity (T), and a term for synthetic accessibility (SA).
Thus, the accronyms are self-explanatory. These exclusion scores (Figure
2 and Table S6) measure deviations from the average values of already
used oral drugs.
SE,ADME2 values have been described to be between 1.2
and 1.5 when studying 1791, 152 and 35 oral drugs,
respectively.140-142, 162 On the other hand, for the
rasagiline derivatives with the highest selection scores, average
SE,ADME2 =1.35, with individual values ranging from
0.6 to 2.9 for the whole set (Table S6, Supporting Information). The
average SE,ADME8 is 5.9, with individual values
ranging from 2.4 to 9.9; the average SE,ADMET was
found to be 7.6, with individual values ranging from 3.7 to 12.7; and
the average SE,ADMETSA is 7.8, with individual values
ranging from 3.8 to 13.3 (Table S6). It is essential to keep in mind,
though, that high values of these scores may arise from either worse or
better behavior (as oral drug-like species) than the average of the
reference set of drugs.