Table 2.
RBP4 Binding Affinity, Functional RBP4-TTR Antagonism, Kinetic Aqueous Solubility, and Liver Microsomal Metabolic Stability Data For [1,2,4]Triazolo[4,3-a]pyridine RBP4 Antagonists
 |
| Compound Number/ Scaffold Core |
R | RBP4 SPAa IC50 (nM) |
RBP4 HTRFa IC50 (nM) |
Kinetic Solubilityb (μM) |
Microsomal Stability (% remaining) |
cLogP | LLE | ||
|---|---|---|---|---|---|---|---|---|---|
| HLMc | RLMd | MLMe | |||||||
| 34/A |  |
4.55 | 22.5 | 8 | 80 | 4.9 | 2.4 | 2.89 | 5.45 |
| 35/A |  |
4.01 | 25.2 | 11 | 81 | 22 | 44 | 3.46 | 4.93 |
| 36/A |  |
3.70 | 12.8 | 25 | 74 | 31 | 32 | 3.17 | 5.26 |
| 37/A |  |
3.97 | 20.6 | 2.5 | 77 | 31 | 2.5 | 3.70 | 4.70 |
| 38/A |  |
3.75 | 28.3 | 1.9 | 85 | 92 | 98 | 3.64 | 4.78 |
| 39/B |  |
4.1 | 67.5 | 9.3 | 53 | 1.6 | 44 | 3.21 | 5.17 |
| 40/B |  |
4.5 | 49.3 | <1.6 | 61 | 2.3 | 3 | 3.78 | 4.56 |
| 41/B |  |
6.0 | 61.7 | 4.5 | 47 | 7.8 | 7.2 | 3.48 | 4.74 |
| 42/B |  |
2.7 | 71.4 | <1.6 | 57 | 39 | 8.2 | 4.01 | 4.55 |
| 43/B |  |
3.4 | 10.6 | <1.6 | 76 | 69 | 61 | 3.95 | 4.51 |
| 48/A |  |
5.14 | 60.9 | 44 | 99 | 82 | 100 | 2.20 | 6.08 |
| 49/A |  |
3.9 | 16.6 | 28.6 | 100 | 57 | 27 | 3.25 | 5.15 |
| 51/B |  |
6.0 | 90.3 | <1.6 | 27 | 31 | 45 | 2.51 | 5.71 |
| 52/B |  |
32.8 | 895 | 84 | 81 | 83 | 72 | 3.16 | 4.32 |
| 53/B |  |
14.6 | 240.6 | 17 | 19 | 19 | 4.2 | 2.85 | 4.98 |
| 54/B |  |
10.0 | 211.5 | <1.6 | 25 | 61 | 40 | 2.80 | 5.20 |
For compounds tested more than twice, IC50 is represented as the mean ± standard deviation. Otherwise, IC50 is shown as the mean of two independent experiments.
Kinetic aqueous solubility measured in PBS, pH 7.4. Verapamil and tamoxifen were used as controls.
HLM = human liver microsomes.
RLM = rat liver microsomes.
MLM = mouse liver microsomes. The compound concentration was 10 μM and incubation time with either human, rat, or mouse microsomes was 30 min. Testosterone was used as a positive control. cLog P is derived from ChemDraw Professional (ChemOffice Professional, CambridgeSoft and PerkinElmer). LLE = lipophilic ligand efficiency: RBP4 SPA pIC50 − cLog P. ND = not determined.