TABLE 2.
Physicochemical and ADMET profile for RG7774.
| M r [Da] | 358.408 |
| PSA [Å2] | 115.9 |
| logD 7.4 | 2.2 |
| LLE | 7.1 |
| LYSA [µg/mL] | 285 |
| THESA/FaSSIF/FeSSIF [µg/mL] | 901/1177/2872 |
| pKa | 2.63 (basic) |
| PAMPA P eff [10−6 cm s−1] | 9.7 (23/18/59)a |
| Chemical stability in aqueous media at pH 1–10 | stable |
| Microsomal CLint [µL min−1 (mg protein)−1] (human/mouse/rat) | 21.7/15.0/25.0 |
| Hepatocyte CL [µL min−1 (10−6 cells)−1] (human/mouse/rat) | 1.7/49.3/37.9 |
| PPB (fu) [%] (human/mouse/rat) | 17.8/4.5/15.8 |
| P-gp efflux ratio (human/mouse) | 2.5/16.2 |
| GSH (human liver microsomes) adducts | none detected |
| CYP inhibition [µM] (3A4/2C19/2C8/2C9/2D6/1A2) | >50/>50/>50/29/>50/>50 |
| hERG IC50 [µM] | >20 |
aAcceptor compartment/membrane/donor compartment [%]. Å: Angström; ADMET: absorption, distribution, metabolism, elimination and toxicity; CL: clearance; CLint: intrinsic clearance; CYP: cytochrome P-450; Da: daltons; FaSSIF: fasted simulated gastrointestinal fluid; FeSSIF: fed simulated gastrointestinal fluid; fu: fraction unbound; GSH: glutathione-stimulating hormone; hERG: human Ether-à-go-go-related gene; IC50: half maximal inhibitory concentration; LLE: ligand-lipophilicity efficiency; logD: octanol/water distribution coefficient; LYSA: lyophilization solubility assay; M r : molecular weight; PAMPA: parallel artificial membrane permeability assay; P-gp: permeability glycoprotein; pKa: acid-base dissociated constant; PSA: polar surface area; THESA: thermodynamic solubility assay.