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.