Design, synthesis and SAR study of hydroxychalcone inhibitors of human β-secretase (BACE1)

Figures & data

Scheme 1.  Preparation of hydroxychalcones.

Table 1.  Importance of the position of a hydroxyl substituent at B-ring.

Compound	Position of OH	IC50^a (μM) to BACE1
1	Position 4	33.00 ± 3.75
2	Position 3	8.03 ± 0.92
3	Position 2	2.45 ± 0.39
HEA^b		0.049 ± 0.011

^aIn all tables, IC₅₀s reported are means of the values of three different experiments. Each IC₅₀ is within threefold of the mean value.

^bHydroxyethylamine, the positive control in the assay demonstrated an IC₅₀ value of 0.049 ± 0.011 μM, see ref. 16 for details.

Table 2.  Diverse compounds at the position 2 of B-ring.

Compound	R	IC50 (μM) to BACE1
3	OH	2.45 ± 0.39
4	OMe	2.63 ± 0.28
5	OCH2CH=CH2	>60
6	Cl	11.40 ± 1.36
7	NO2	>60

Table 3.  Importance of the positions of hydroxyl substituents at A-ring.

Compound	Position of OH	IC50 (μM) to BACE1
3	Positions 2′ and 4′	2.45 ± 0.39
8		>60
9	Position 2′	>60
10	Position 3′	30.4 ± 4.25
11	Position 4′	58.1 ± 4.92
12	Positions 2′ and 3′	21.8 ± 2.31
13	Positions 2′ and 5′	41.8 ± 5.52
14	Positions 2′ and 6′	15.6 ± 1.83
15	Positions 3′ and 4′	11.8 ± 1.35
16	Positions 3′ and 5′	19.4 ± 2.33

Table 4.  Importance of the positions of hydroxyl substituents at B-ring.

Compound	Position of OH	IC50 (μM) to BACE1
3	Position 2	2.45 ± 0.39
17	Positions 2 and 3	0.27 ± 0.05
18	Positions 2 and 4	0.62 ± 0.08
19	Positions 2 and 5	1.94 ± 0.20
20	Positions 2 and 6	1.71 ± 0.21
21	Positions 3 and 4	2.37 ± 0.34
22	Positions 3 and 5	2.08 ± 0.38

Stachel SJ, Coburn CA, Steele TG, Jones KG, Loutzenhiser EF, Gregro AR, Rajapakse HA, Lai MT, Crouthamel MC, Xu M, Tugusheva K, Lineberger JE, Pietrak BL, Espeseth AS, Shi XP, Chen-Dodson E, Holloway MK, Munshi S, Simon AJ, Kuo L, Vacca JP. Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). J Med Chem 2004;47:6447–6450.

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