文档介绍：BACE-1/OM99-2
Substrate based inhibitor
S1
S3’
S4’
S2’
S1’
S4
S3
S2
BACE-1 Inhibitors-Current Status
I. Statin & Homostatin Peptidic BACE-1 Inhibitors
II. Hydoxyethylamine BACE-1 Inhibitors
III. Other Peptidomimetic BACE-1 Inhibitors
IV. Non-Peptidic Small Molecular BACE-1 Inhibitors
Since the discovery of BACE-1 enzyme, there are ~ 100
patent applications and publications for BACE-1 inhibitors
up to today. It has been classified as following series:
BACE-1 Inhibitors
Statin & Homostatin Peptidic
Tang (Oklahoma Medical Research Foundation) & Ghosh (Univ. of Illinois)
J. Am. Chem. Soc. 2000, 122, 3522
BACE-1 Inhibitors
I. Statin & Homostatin Peptidic (Elan Pharm./Pharmacia)
Elan Pharm./Pharmacia-Upjohn
>25 patent applications from 2000-now
Majorly in Statin/Homostatin & Hydroxy ethylamines
WO 00/077030
WO 03/006021
IC50 = 120 nM
Statin Inhibitors:
BACE-1 Inhibitors
I. Statin & Homostatin Peptidic (Elan Pharm./Pharmacia)
Homostatin Inhibitors:
WO 01/070672
J. Med. Chem. 2004, 47, 158
IC50 = 26 nM
WO 02/0100820
WO 03/103652
WO 03/103653
R = Bn, O(CH2)3OCH3
X = CN, N
BACE-1 Inhibitors
I. Statin & Homostatin Peptidic (panies)
Homostatin Inhibitors:
R1
BACE-1
Ki (nM)
Cat D.
Ki (nM)
Renin
Ki (nM)
CH3
70
29
24
CH2OH

13
11
CH2OAc

COOH

80
74
WO 03/099202
. Med. Chem. 2004, 14, 601
Merck:
Glaxo-Smith-Kline:
R1 = H, OH, Alkoxy, Phenyl, Phenoxy
R2 =
WO 03/045903
WO 03/045913
Sunesis:
WO 03/106405
BACE-1 Inhibitors
II. Hydoxyethylamine BACE-1 Inhibitors
very active area
>20 patent applications
Elan/Pharmacia, Bristol-Myers Squibb, Schering-Plough
Merck, Novartis, GlaxoSmithKline.
WO 02/002505
Elan/Pharmacia:
Preferred R:
preferred
H, Et, OMe, alkynyl
halogens, CF3
R=Alkyl, heteroaryl
WO 03/040095
WO 02/002512
BACE-1 Inhibitors
II. Hydroxy Ethylamines
Bristol-Myers Squibb:
R1 = alkyl, alkoxyalkyl
X = CO, CO2, CONH, SO1, 2
WO 04/013098
R2 = alkyl,
alkoxyalkyl
R3 =
BACE-1 In