Table 4.
In Vitro and In Vivo ADMET Data for Compound 32 Compared to Known P2Y14R Antagonist 5a
| test | 5b | 32 |
|---|---|---|
| simulated intestinal fluid (t1/2, min) | >240 | >240 |
| simulated gastric fluid (t1/2, min) | >240 | 161 |
| CYP1A2 (IC50, μM) | >30 | >30 |
| CYP2C9 (IC50, μM) | >30 | 10.4 |
| CYP2C19 (IC50, μM) | >30 | >30 |
| CYP2D6 (IC50, μM) | >30 | >30 |
| CYP3A4 (IC50, μM) | >30 | >30 |
| plasma stability (species)c (t1/2, min) | >240 (h), >240 (r), >240 (m) | >240 (r), >240 (m) |
| microsomal stability (t1/2, min) | 145 (m), 108 (r), 145 (h) | >240 (h), 47.7 (r), >240 (m) |
| hERG, IC50 (μM)d | 0.166 (fluorescent) | >30 (patch clamp) |
| HepG2 cell toxicity, IC50 μM) | >30 | 8.47 |
| t1/2 (r)e | 0.20 (0.5 mg kg −1, i.v.) | 7.23 (1.0 mg kg−1, i.p.) |
| aqueous solubilityf (pH 7.4, μg mL−1) | 138 ± 4 | 7.63 ± 1.93 |
| aqueous solubilityf (pH 4.0, μg mL−1) | NDg | 0.14 ± 0.02 |
a
Procedures are in the Supporting Information and in Yu et al.1 Dosing formulation: for i.v., DMSO/20% 2-hydroxypropyl-β-cyclodetrin (Sigma-Aldrich, 10:90); for i.p., DMSO/Kolliphor EL (Sigma-Aldrich)/PBS (15:15:70).
b
Data determined by Yu et al.1
c
Species tested for plasma stability were human, rat, and mouse; species as indicated for microsomal stability.
d
Method noted in parentheses.
e
By administration in rat (plasma half-life, h). See Table 5 for complete results for 32.
f
Mean ± SD, pION method.
g
ND, not determined.