Table 7.
Summary of in Vitro ADME Profiles for 43 and 52
| profiling assays | 43 (NCATS-SM1440) | 52 (NCATS-SM1440) |
|---|---|---|
| liver microsomal T1/2 (human, mouse, and rat) | >120 min | >120 min |
| liver cytosolic T1/2 (human, mouse, and rat) | >120 min | >120 min |
| metabolic stability (hepatocytes-rat, dog, and mouse) | >150 min | >150 min |
| plasma stability T1/2 | >240 min | >240 min |
| PAMPA permeability | 10.4 × 10−6 (cm/s) | 2.2 × 10−6 (cm/s) |
| PAMPA-BBB permeability | 16 × 10−6 (cm/s) | 9.6 × 10−6 (cm/s) |
| aq solubility at pH 7.4 | >70 μwg/mL | >70 μg/mL |
| plasma protein binding (Fu = % fraction unbound) | 0 (human), 0.7 (mouse) | 0 (human), 4.4 (mouse) |
| CYP450 inhibition (isozyme) | 2C8: 80% @10 μM, 2B6: 46% @10 μM, 2C9: 45% @10 μM | 2C8: 7.5 μM, 2B6: 14 μM |
| metabolite ID (in vitro) | no significant phase I or II metabolites | no significant phase I or II metabolites |
| CYP induction | no induction at 10 μM | no induction at 10 μM |
| PXR and AhR Activation | <2-fold activation up to 10 μM | <2-fold activation up to 10 μM |
| reactive metabolite formation | no GSH adducts formed | no GSH adducts formed |
| hERG (patch clamp) | >10 μM | >10 μM |
| Ames | negative | negative |
Aqueous kinetic solubility (PBS buffer) and PAMPA permeability, liver microsomal & cytosolic stability studies, were conducted at NCATS. Mouse plasma stability studies were conducted at Pharmaron Inc. and involved five-time points. The microsomal stability data [mouse liver microsomes (MLM), human liver microsomes (HLM), and mouse hepatocytes] were conducted at QuintaraBio and represent the stability in the presence of NADPH and UDPGA. The parent compound was monitored at five-time points.