Table 4.
ADME/PK profiles of the MCA-based HDAC6is 20 and 63.a
| Compound Structure |
20 | 63 | SAHA | |
|---|---|---|---|---|
 |
 |
 |
||
| HDAC isoform (IC50, μM) | HDAC6 | 0.11 | 0.02 | 0.03 |
| HDAC1 | 1.08 | 3.22 | 0.03 | |
| SI | 9.8 | 161 | 1 | |
| LogD at 37°C | 2.19 ± 0.1 | 2.64 ± 0.1 | 1.46 ± 0.2 | |
| Solubility (μg/mL) | PBS (pH 7.4, 37°C, 24 h) | ~120 | ~150 | ~400 |
| HCl (pH 1.2, 37°C, 24 h) | ~1000 | ~1000 | ~100 | |
| Permeability in Caco-2 cells | Papp (A-B) (10−6, cm/s) | 7.33 ± 0.3 | 15.0 ± 0.4 | 3.00 ± 0.2 |
| Papp (B-A) (10−6, cm/s) | 10.0 ± 0.4 | 24.7 ± 0.12 | 6.33 ± 0.3 | |
| Efflux ratio | 1.36 | 1.64 | 2.11 | |
| Plasma stability (t1/2, min) | Human | 77 | 79 | 75 |
| Mouse | 173 | 58 | 115 | |
| Porcine | 89 | 69 | 87 | |
| Rat | 99 | 92 | 86 | |
| Liver microsomal stability (t1/2, min) | Human | 68 | 83 | n/a |
| Dog | 43 | 72 | n/a | |
| Rat | 70 | 66 | n/a | |
| PK parameters in mice (400 mg/kg, IP) | Cmax (μmol/L) | 1.54 ± 0.26 | 1.81 ± 0.34 | n/a |
| tmax (h) | 0.5 | 0.5 | n/a | |
| AUC (μmol/L × h) | 4.23 ± 0.43 | 4.97 ± 0.60 | n/a | |
| t1/2 (h) | 1.98 ± 0.21 | 2.20 ± 0.33 | n/a | |
| CL (L/h) | 4.87 ± 0.2 | 4.05 ± 0.15 | n/a |