Table 3. SAR of 12–16.
|
in
vitro ADME |
rat ivd | rat poe | cyno ivf |
cyno poe |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| compd | HPK1 Ki (nM) | p-SLP76 IC50 (nM) | IntCL (L h–1 kg–1) | Caco-2 Pmb | fu (%)c | CL (L h–1 kg–1) | AUC (nM h) | CL (L h–1 kg–1) | Vdss (L h–1 kg–1) | T1/2 (h) | AUC (nM h) | F (%) |
| 12 | 2.7 | 91 | <0.5 | 1.1 | 41 | 7.1 | 456 | 1.2 | 4.6 | 5.5 | 759 | 7 |
| 13a | 4.0 | 94 | <0.5 | 0.2 | 49 | 5.6 | 799 | 1.1 | 7.6 | 8.6 | 3930 | 50 |
| 14a | 4.6 | 138 | <0.5 | 0.4 | 50 | 4.8 | 1460 | 0.54 | 4.6 | 8.9 | 7840 | 55 |
| 15 | 5.0 | 137 | <0.5 | 1.4 | 61 | 6.1 | 761 | 0.66 | 3.9 | 6.3 | 1640 | 16 |
| 16 | 4.1 | 146 | 0.5 | 3.1 | 43 | 6.1 | 1100 | 0.95 | 4.0 | 6.0 | 9770 | 96 |
a
Single enantiomer.
b
In units of 10–6 cm/s.
c
Fraction unbound in human plasma.
d
1.5 mg/kg dosing.
e
3.0 mg/kg dosing.
f
1.0 mg/kg dosing.