P3 cap modified Phe*-Ala series BACE inhibitors

被引：35

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

[11] Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor
Hong, L
Koelsch, G
Lin, XL
Wu, SL
Terzyan, S
Ghosh, AK
Zhang, XC
Tang, J
[J]. SCIENCE, 2000, 290 (5489) : 150 - 153
[12] Mernapsin 2 (β-secretase) as a therapeutic target
Hong, L
Turner, RT
Koelsch, G
Ghosh, AK
Tang, J
[J]. BIOCHEMICAL SOCIETY TRANSACTIONS, 2002, 30 : 530 - 534
[13] Identification of a novel aspartic protease (Asp 2) as β-secretase
Hussain, I
Powell, D
Howlett, DR
Tew, DG
Week, TD
Chapman, C
Gloger, IS
Murphy, KE
Southan, CD
Ryan, DM
Smith, TS
Simmons, DL
Walsh, FS
Dingwall, C
Christie, G
[J]. MOLECULAR AND CELLULAR NEUROSCIENCE, 1999, 14 (06) : 419 - 427
[14] Current drug targets for Alzheimer's disease treatment
Lahiri, DK
Farlow, MR
Greig, NH
Sambamurti, K
[J]. DRUG DEVELOPMENT RESEARCH, 2002, 56 (03) : 267 - 281
[15] Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3SAR
Lamar, J
Hu, JD
Bueno, AB
Yang, HC
Guo, DQ
Copp, JD
McGee, J
Gitter, B
Timm, D
May, P
McCarthy, J
Chen, SH
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (01) : 239 - 243
[16] ElogPoct:: A tool for lipophilicity determination in drug discovery
Lombardo, F
Shalaeva, MY
Tupper, KA
Gao, F
Abraham, MH
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (15) : 2922 - 2928
[17] Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation
Luo, Y
Bolon, B
Kahn, S
Bennett, BD
Babu-Khan, S
Denis, P
Fan, W
Kha, H
Zhang, JH
Gong, YH
Martin, L
Louis, JC
Yan, Q
Richards, WG
Citron, M
Vassar, R
[J]. NATURE NEUROSCIENCE, 2001, 4 (03) : 231 - 232
[18] Roggo Silvio, 2002, Current Topics in Medicinal Chemistry, V2, P359, DOI 10.2174/1568026024607490
[19] The origins of Alzheimer disease - A is for amyloid
Selkoe, DJ
[J]. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2000, 283 (12): : 1615 - 1617
[20] Translating cell biology into therapeutic advances in Alzheimer's disease
Selkoe, DJ
[J]. NATURE, 1999, 399 (6738) : A23 - A31

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