Table 5.
Solubility and Selected ADME Properties for Chosen Analogues
| Analogue | Solubilitya (μM) |
Solubilitya (μg/mL) |
LogDb | Caco-2 Permeabilityc mean A->B |
Caco-2 Permeabilityc mean B->A |
Microsomal stabilityd |
hERG FastPatche |
|---|---|---|---|---|---|---|---|
| 2 | 30.1 | 5.6 | 2.42 | 1.0 | 0 | 8/63 | 13.2% |
| 16 | 18.6 | 5.0 | 3.1 | 7.9 | 4.8 | 10/67 | 5.5% |
| 29 | 240.4 | 46.4 | 2.54 | 8.4 | 9.0 | 1/64 | 3.4% |
| 31 | 5.0 | 1.5 | ND* | ND* | ND* | ND* | 7.8% |
| 32 | 3.7 | 1.1 | ND* | ND | ND | ND | ND |
| 33 | 89.1 | 28.0 | 2.91 | 7.9 | 2.7 | 20/51 | 29.4% |
| 34 | 11.5 | 3.5 | 2.92 | 4.0 | 1.8 | 3/56 | 83.9% |
| 35 | 122.2 | 36.9 | 2.92 | 9.4 | 3.4 | 12/52 | 57.2% |
kinetic solubility analysis was performed by Analiza Inc. and are based upon quantitative nitrogen detection as described (www.analiza.com). The data represents results from three separate experiments with an average intraassay %CV of 4.5%.
LogD analysis was performed by Analiza Inc. and are based upon octanol/buffer partitioning and quantitative nitrogen detection of sample content as described (www.analiza.com). The data represents results from three separate experiments and is corrected to calibration standards and adjusted to account for fixed amounts of DMSO.
Caco-2 permeability analysis was performed by Apredica Inc. and are based upon monolayer Caco-2 cells applied to collagen-coated BioCoat Cell Environment at 24,500 cells per well as described (www.apredica.com). Data are expressed in Papp (apparent permeability) in 10−6 cm s−1. Atenolol was used as a low permeability control (mean A->B = 1.2 and mean B->A = 1.2) and propanolol was used as a high permeability control (mean A->B = 20.3 and mean B->A = 17.4).
Microsomal stability analysis was performed by Apredica Inc. and are based upon duplicate incubations of test reagent with liver microsomes (human and rat; only human data is shown) over 60 minutes at 37 °C as described (www.apredica.com). LC/MS/MS is utilized to quantitate remaining test reagent and the data is reported as % remaining. Analysis in the absence and presence of NADPH was performed to assess NADPH free degradation. Data is listed as NADPH (+) degradation/NADPH (−) degradation.
hERG FastPatch analysis was performed by Apredica Inc. using an automated patch clamp electrophysiological procedure using HEK293 cells stably transfected with hERG cDNA as described (www.apredica.com). Test reagents were applied at standard concentrations (10 μM) and data is recorded as mean % inhibition from three separate experiments.