TABLE 2.
| |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Compd | R1 | R2 | R3 | cLogP | FabI Inhibitiona | Microsomal Stability | Serum/Microsomal Free Fraction | Hepatic Clearance | Hepatic Extraction Ratio | ||
| |||||||||||
IC50 (μM) | t1/2 (min) | Clint, app (μl/min/mg) | fu, s | fu, m | Clh (ml/min/kg) | ||||||
23 | CH2 | CH3 | 3′-H, 4′-Cl, 5′-Cl, 6′-H, 7′-H | 5.77 | 0.043 | 20.0 | 69 | 0.001 | 0.017 | 7 | 0.1 |
24 | CH2 | H | 3′-H, 4′-H, 5′-OCH3, 6′-H, 7′-H | 4.28 | 0.84 | 2.9 | 474 | 0.022 | 0.299 | 38 | 0.4 |
25 | CH2 | H | 3′-H, 4′, 5′-OCH2O, 6′-H, 7′-H | 4.22 | 2.2 | 4.6 | 304 | 0.021 | 0.263 | 30 | 0.3 |
26 | CH2 | H | 3′-H, 4′-CH3, 5′-OCH3, 6′-H, 7′-H | 4.74 | 0.005 | 2.1 | 672 | 0.006 | 0.086 | 45 | 0.5 |
27 | O | CH3 | 3′-H, 4′-Cl, 5′-Cl, 6′-H, 7′-H | 4.28 | 0.89 | 14.8 | 94 | 0.034 | 0.393 | 13 | 0.1 |
28 | O | H | 3′-H, 4′-H, 5′-OCH3, 6′-H, 7′-H | 2.78 | 5.3 | 5.9 | 235 | 0.183 | 0.816 | 47 | 0.5 |
29 | O | H | 3′-H, 4′, 5′-OCH2O, 6′-H, 7′-H | 2.73 | 11.8 | 20.4 | 68 | 0.201 | 0.791 | 24 | 0.3 |
30 | O | H | 3′-H, 4′-CH3, 5′-OCH3, 6′-H, 7′-H | 3.24 | 0.12 | 1.4 | 980 | 0.158 | 0.812 | 72 | 0.8 |
31 | O | H | 3′-H, 4′-OCH3, 5′-OCH3, 6′-H, 7′-H | 2.60 | 22.4 | 18.6 | 75 | 0.293 | 0.855 | 31 | 0.3 |
FabI IC50 values determined per published procedures (Hevener et al. 2012) with reduced FabI concentration of 10 nM.