Table 7.

BBB-permeability, mouse and human liver microsomal stability, key pharmacokinetic properties for selected compounds^a

Entry	MLMt 1/2(min)	HLM t 1/2(min)	In vivo plasma t 1/2 (h)a	Brain- to- plasma ratiob	Permeability across MDR1-MDCK cell linec	Efflux ratio (B-A / A-B)	MPO scored (Desired score for CNS permeability ≥ 4)
1	10	11	1.7 (ip/po, 10 mg/kg dose)	1.7	B-A: 27.1 × 10−6 cm/s A-B: 25.4 × 10−6 cm/s	1.1	4.7
3	>60	>60	> 6h (po, 10mg/kg)	0.02	B-A: 0.12 × 10−6 cm/s A-B: 0.41 × 10−6 cm/s	0.3	5.0
8c	2.9	ND	<1h (ip, 10mg/kg)	0.5	B-A: 51.0 × 10−6 cm/s A-B: 19.8 × 10−6 cm/s	2.6	3.8
8g	2.9	ND	< 1h (ip, 10mg/kg)	ND	B-A: 55.3 × 10−6 cm/s A-B: 20.6 × 10−6 cm/s	2.7	3.7
14a	6.5	ND	< 1h (ip, 10mg/kg)	0.16	B-A: 71.1 × 10−6 cm/s A-B: 4.54 × 10−6 cm/s	16	4.3
20o	17	87.7	1.1 h (IP, 10 mg/kg) & 2.4 h (po, 50 mg/kg)	0.4	B-A: 21.5 × 10−6 cm/s A-B: 10.2 × 10−6 cm/s	2.1	3.6
In the presence of a pgp-inhibitor (verapamil)
20o					B-A: 22.2 × 10−6 cm/s A-B: 13.2 × 10−6 cm/s	1.7

^aMLM = mouse liver microsomes; HLM = human liver microsomes. In liver microsomal stability tests, 1 μM compound test compound was incubated with 0.5 mg/mL liver microsomes for compounds 1and 3. However, other compounds in the table were incubated with 0.125 mg/mL liver microsomal concentration. The plasma half-life is estimated based on the 3-time point B/P ratio studies conducted with single injection of 10 mg/kg dose to male mice. A full-scale pharmacokinetic study with 8-time points was done for selected compounds (1, 3, 20o).

^bBrain-to-plasma are derived from peak concentrations observed at 0.5 h after injection in to mice.

^cBBB potential was determined using MDR1-expressed cell monolayers. All these studies are conducted at CRO laboratories following industry standard procedures.

^dSee Table 1 for the physicochemical properties used to calculate the MPO score.