Table 2. Optimization of the Upper Phenyl Ring Part in (4R, 6S)-Isomer^a,b.

				in vivo CSI (1 mg/kg, % inhibition)
compd	R	SSI (IC50 nM)	CSI (IC50 nM)	1 h	4 h	7 h
19	OMe	1.6	38	88	78	45
20	OCF3	0.7	28	77	67	48
21	Et	0.36	18	76	57	21
22	Me	0.85	46	87	69	45
23	Cl	1.1	19	93	77	55

^aThe same configuration as TAK-475.

^bSSI: squalene synthase inhibitory activity. CSI: cholesterol synthesis inhibitory activity in rat hepatic cell. In vivo CSI: hepatic cholesterol inhibition (%) in rat at 1, 4, and 7 h after 1 mg/kg single dose oral administration.