P3 cap modified Phe*-Ala series BACE inhibitors

被引：36

作者：

Chen, SH ^{[1
]}

Lamar, J ^{[1
]}

Guo, DQ ^{[1
]}

Kohn, T ^{[1
]}

Yang, HC ^{[1
]}

McGee, J ^{[1
]}

Timm, D ^{[1
]}

Erickson, J ^{[1
]}

Yip, Y ^{[1
]}

May, P ^{[1
]}

McCarthy, J ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Discovery Chem Div & Technol, Lilly Corp Ctr, Indianapolis, IN 46285 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 01期

关键词：

D O I：

10.1016/j.bmcl.2003.09.085

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3 NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC50 < 50 nM) and whole cell activities (IC50 similar to 1 muM). (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：245 / 250

页数：6

共 28 条

[1] Alzheimer's disease: a review of the disease, its epidemiology and economic impact [J].

Alloul, K ;

Sauriol, L ;

Kennedy, W ;

Laurier, C ;

Tessier, G ;

Novosel, S ;

Contandriopoulos, A .

ARCHIVES OF GERONTOLOGY AND GERIATRICS, 1998, 27 (03) :189-221

[2]

Boyd J. G., 2002, An inhibitor of beta amyloid cleavage enzyme, Patent No. [EP-1233021, 1233021]

[3]

BROOKS D, UNPUB BIOORG MED CHE

[4]

CAPRINO LA, 1999, TETRAHEDRON, V55, P6813

[5] PYBOP - A NEW PEPTIDE COUPLING REAGENT DEVOID OF TOXIC BY-PRODUCT [J].

COSTE, J ;

LENGUYEN, D ;

CASTRO, B .

TETRAHEDRON LETTERS, 1990, 31 (02) :205-208

[6] Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain [J].

Dovey, HF ;

John, V ;

Anderson, JP ;

Chen, LZ ;

Andrieu, PD ;

Fang, LY ;

Freedman, SB ;

Folmer, B ;

Goldbach, E ;

Holsztynska, EJ ;

Hu, KL ;

Johnson-Wood, KL ;

Kennedy, SL ;

Kholedenko, D ;

Knops, JE ;

Latimer, LH ;

Lee, M ;

Liao, Z ;

Lieberburg, IM ;

Motter, RN ;

Mutter, LC ;

Nietz, J ;

Quinn, KP ;

Sacchi, KL ;

Seubert, PA ;

Shopp, GM ;

Thorsett, ED ;

Tung, JS ;

Wu, J ;

Yang, S ;

Yin, CT ;

Schenk, DB ;

May, PC ;

Altstiel, LD ;

Bender, MH ;

Boggs, LN ;

Britton, TC ;

Clemens, JC ;

Czilli, DL ;

Dieckman-McGinty, DK ;

Droste, JJ ;

Fuson, KS ;

Gitter, BD ;

Hyslop, PA ;

Johnstone, EM ;

Li, WY ;

Little, SP ;

Mabry, TE ;

Miller, FD ;

Ni, B .

JOURNAL OF NEUROCHEMISTRY, 2001, 76 (01) :173-181

[7] CONTRASTERIC CARBOXIMIDE HYDROLYSIS WITH LITHIUM HYDROPEROXIDE [J].

EVANS, DA ;

BRITTON, TC ;

ELLMAN, JA .

TETRAHEDRON LETTERS, 1987, 28 (49) :6141-6144

[8] ASYMMETRIC ALKYLATION REACTIONS OF CHIRAL IMIDE ENOLATES - A PRACTICAL APPROACH TO THE ENANTIOSELECTIVE SYNTHESIS OF ALPHA-SUBSTITUTED CARBOXYLIC-ACID DERIVATIVES [J].

EVANS, DA ;

ENNIS, MD ;

MATHRE, DJ .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1982, 104 (06) :1737-1739

[9] Presenilin function:: connections to Alzheimer's disease and signal transduction [J].

Fraser, PE ;

Yu, G ;

Lévesque, L ;

Nishimura, M ;

Yang, DS ;

Mount, HTJ ;

Westaway, D ;

St George-Hyslop, PH .

NEURONAL SIGNAL TRANSDUCTION AND ALZHEIMER'S DISEASE, 2001, 67 :89-100

[10] Structure-based design:: Potent inhibitors of human brain memapsin 2 (β-secretase) [J].

Ghosh, AK ;

Bilcer, G ;

Harwood, C ;

Kawahama, R ;

Shin, D ;

Hussain, KA ;

Hong, L ;

Loy, JA ;

Nguyen, C ;

Koelsch, G ;

Ermolieff, J ;

Tang, J .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (18) :2865-2868

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