Table 5.

In Vitro Properties of Select Compounds

	24	25	26	27
Thermodynamic Solubilities (μM)a pH 7 FESSIF SGF	37 80 9015	0.2 11 342	5 22 46	38b 19b 9446b
Caco2 AB/BA (cm/sec*10−6)c	1.8/20	5.8/21	7.7/25	5.2/25
Microsomal Stability Clint (mL/min/kg)d Rat Dog Human	14 2 4	22 77 13	8 0 4	15 5 0
Hepatocytes Stability Clint (mL/min/kg)e Rat Dog Human	5 4 0	34 12 3	5 9 2	6 7 3
Protein Binding (% bound)f Rat Dog Human	97 72 97	99 98 99	95 90 96	99 98 98

^aThermodynamic aqueous solubility (μM) in phosphate buffer (100 mM) at pH 7.0, FeSSIF (Fed State Simulated Intestinal Fluid) at pH 5.0, or SGF (fasted state Simulated Gastrointestinal Fluid) at pH 1.6; shaken for 1 hour then equilibrated overnight at RT.

^bThermodynamic aqueous solubilities for the crystalline most stable polymorph of 27, identified during later development, in phosphate buffer (50 mM) at pH 6.8, FeSSIF or SGF, shaken for 24 hours at 25 °C (phosphate buffer) or 37 °C (FeSSIF and SGF).

^cPermeability in Caco-2 cells AB (apical to basolateral) and BA (basolateral to apical) movement of 10 μM test compound in 21 day cultured Caco-2 cells ((cm/s) × 10⁻⁶).

^dLiver microsomal intrinsic clearance (mL/min/kg protein).

^eLiver hepatocyte intrinsic clearance (mL/min/kg protein).

^fPlasma protein binding determined by equilibrium dialysis.