Table 1. SAR of Phenyl Ring Substituents^a.

					μL/min/mgd
compdb	R1	R2	BACE IC50 (nM)c	cell IC50 (nM)a	RLM	HLM	LLC-PK1 Papp (×10–6 cm/s)
4	H	H	5.8 ± 6.3	3.1 ± 4.2	241	465	22
16	4-F	H	5.0 ± 3.0	12 ± 6.1	180	107	21
17	3-F	H	1.0 ± 0.47	1.8 ± 1.2	227	621	16
18	2-F	H	3.6 ± 0.86	5.1 ± 4.3	206	342	13
19	4-Cl	H	8.3 ± 2.7	13 ± 9.1	160	443	21
20	4-OCF3	H	14 ± 1.3	65 ± 4.3	101	181
21	3-F	5-F	6.9 ± 8.7	6.6 ± 7.5	186	921	15
22	3-CF3	H	2.4 ± 0.97	4.0 ± 1.6	179	308	12
23	4-F	2-F	6.5 ± 5.3	18 ± 0.41	173	71
24	4-F	3-F	2.0	2.4 ± 1.1			16
25	4-F	3-CH3	4.0 ± 3.0	4.6 ± 2.6	>399	829	15
26	4-F	3-CF3	11 ± 14	18 ± 8.8	116	134	12
27	4-F	3-OCF3	2.1	26 ± 18	220	360	8.6
28	4-F	3-CN	2.4 ± 0.06	4.5 ± 1.1	185	188
29	4-F	3-OCH3	4.5 ± 0.99	7.6 ± 3.4	165	628	20
30	4-CH3	3-F	0.99 ± 0.37	2.2 ± 0.82	155	>399	18
31	4-OCH3	3-F	3.6 ± 0.73	8.5 ± 6.4	258	162	28
32c	4-CF3	3-F	44 ± 11	160	121	443	16

^aAll values lacking standard deviations were measured as single data points.

^bAll compounds were >95% pure by HPLC and characterized by ¹H NMR and HRMS.

^cCompound is mixture of diastereomers (1:1, 2S,3R and 2R,3S).

^dCompounds are incubated with microsomes for 30 min at a concentration of 1 μM.