Table 3.
Properties of Amidomethyl Ester Prodrugs 37a–37ca
| compound (molecular charge, pH 7) |
MW, TPSA (Å2) |
cLogPb | parent drug |
t1/2 (min, mean ± SEM) for esterase cleavagec |
|---|---|---|---|---|
| 37a (+1) | 577.2, 86.6 | 4.59 | 3a | 20.2 ± 1.9 |
| 37b (uncharged) | 574.6, 88.4 | 5.65 | 32 | >72 (32.6 ± 0.9%)d |
| 37c (uncharged) | 602.7, 66.9 | 6.27 | 1b | >72 (27.2 ± 0.3%)d |
a
Structures are shown in Scheme 6.
b
cLogP calculated using the ALOGPS 2.1 program (www.vcclab.org/lab/alogps/).57
c
At pH 7.3 in the aqueous medium in the presence of PLE. See Experimental Procedures and Supporting Information (Figures S7-S9) for conditions and graphical representation of results. The prodrugs are stable under the same incubation conditions for 24 h in the absence of PLE.
d
Percent cleavage at 72 h in parentheses.