Table 6.
ADME properties of selected CK1δ/ε inhibitors
| № | clogD pH 7.4[a] | Solubility (μM)[b] | Microsome stability, min (H/M/R)[c] | CYP % inhibition[d] | |||
|---|---|---|---|---|---|---|---|
| 1A2 | 2C9 | 2D6 | 3A4 | ||||
| 13 | 3.6 | 0.1 | 18/5/17 | 12 | 62 | −3 | 37 |
| 12 | 2.7 | - [e] | 16/3/5 | 40 | 49 | 14 | 76 |
| 16 | 3.7 | 0.4 | 17/5/10 | 23 | 89 | 47 | 72 |
| 17 | 3.7 | 0.1 | 26/5/27 | −48 | 42 | −2 | 38 |
| 18 | 4.4 | 0.3 | 12/3/6 | −41 | 73 | 8 | 64 |
| 22 | 2.6 | - [e] | 13/2/4 | 46 | 41 | 47 | 34 |
| 23 | 3.0 | - [e] | 15/2/6 | 91 | 84 | 53 | 62 |
| 25 | 2.8 | 0.1 | 25/5/9 | 96 | 95 | 67 | 86 |
| 28 | 3.0 | 28 | 36/4/11 | −1 | 21 | 47 | 44 |
| 29 | 3.3 | 0.4 | 20/5/9 | 61 | 53 | 50 | 74 |
| 31 | 3.4 | 0.1 | 32/12/9 | −9 | 31 | 10 | 18 |
| 40 | 3.1 | - [e] | 9/3/10 | 97 | 96 | 79 | 86 |
| 42 | 2.6 | 1.6 | 5/1/4 | 30 | 44 | 67 | 60 |
| 43 | 3.9 | - [e] | 55/16/26 | 90 | 91 | 80 | 88 |
| 44 | 2.3 | 2.8 | 19/5/18 | -[e] | -[e] | -[e] | -[e] |
| 49 | 2.9 | 1.1 | 22/7/9 | 91 | 92 | 62 | 85 |
| 50 | 3.5 | 0.1 | 16/3/- [e] | 59 | 61 | 31 | −38 |
| 51 | 4.4 | 0.1 | 30/9/- [e] | 66 | 52 | 42 | −12 |
| 58 | 3.1 | - [e] | - [e] | 68 | 31 | 1 | −17 |
| 59 | 3.4 | - [e] | - [e] | 74 | 74 | 18 | 74 |
| 61 | 3.4 | - [e] | 6/2/n.d. | 37 | 35 | −12 | −31 |
| 62 | 4.3 | - [e] | 15/6/- [e] | 85 | 67 | 38 | −51 |
| sunitinib | 46/13/30 | ||||||
[a]
Calculated with Pipeline Pilot workflow application (Accelrys) at pH 7.4.
[b]
Solubility in pH 7.4 phosphate buffered saline.
[c]
Microsome stability using human, mouse and rat liver microsomes, with sunitinib as the reference, half life in 1 mg/ml hepatic microsomes.
[d]
Cytochrome P450 inhibition assay.
[e]
Not determined.