Discovery of amide and heteroaryl isosteres as carbamate replacements in a series of orally active γ-secretase inhibitors

被引：43

作者：

McBriar, Mark D. ^{[1
]}

Clader, John W. ^{[1
]}

Chu, Inhou ^{[1
]}

Del Vecchio, Robert A. ^{[1
]}

Favreau, Leonard ^{[1
]}

Greenlee, William J. ^{[1
]}

Hyde, Lynn A. ^{[1
]}

Nomeir, Amin A. ^{[1
]}

Parker, Eric M. ^{[1
]}

Pissarnitski, Dmitri A. ^{[1
]}

Song, Lixin ^{[1
]}

Zhang, Lili ^{[1
]}

Zhao, Zhiqiang ^{[1
]}

机构：

[1] Schering Plough Res Inst, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 01期

关键词：

gamma-secretase; Alzheimer's disease;

D O I：

10.1016/j.bmcl.2007.10.092

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of A beta levels upon oral dosing in a transgenic murine model of Alzheimer's disease. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：215 / 219

页数：5

共 13 条

[1] Tetrahydroquinoline sulfonamides as γ-secretase inhibitors
Asberom, Theodros
Bara, Thomas A.
Clader, John W.
Greenlee, William J.
Guzik, Henry S.
Josien, Hubert B.
Li, Wei
Parker, Eric M.
Pissarnitski, Dmitri A.
Song, Lixin
Zhang, Lili
Zhao, Zhiqiang
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (01) : 205 - 207
[2] Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset
Brookmeyer, R
Gray, S
Kawas, C
[J]. AMERICAN JOURNAL OF PUBLIC HEALTH, 1998, 88 (09) : 1337 - 1342
[3] A COMPARISON OF (CHLOROMETHYL)ZINC AND (IODOMETHYL)ZINC CYCLOPROPANATION REAGENTS
DENMARK, SE
EDWARDS, JP
[J]. JOURNAL OF ORGANIC CHEMISTRY, 1991, 56 (25) : 6974 - 6981
[4] Inhibition of γ-secretase as a therapeutic intervention for Alzheimer's disease -: Prospects, limitations and strategies
Evin, Genevieve
Sernee, Marijke Fleur
Masters, Colin L.
[J]. CNS DRUGS, 2006, 20 (05) : 351 - 372
[5] Medicine - The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics
Hardy, J
Selkoe, DJ
[J]. SCIENCE, 2002, 297 (5580) : 353 - 356
[6] Small conformationally restricted piperidine N-arylsulfonamides as orally active γ-secretase inhibitors
Josien, Hubert
Bara, Thomas
Rajagopalan, Murali
Asberom, Theodros
Cladera, John W.
Favreau, Leonard
Greenlee, William J.
Hyde, Lynn A.
Nomeir, Amin A.
Parker, Eric M.
Pissarnitski, Dmitri A.
Song, Lixin
Wong, Gwendolyn T.
Zhang, Lili
Zhang, Qi
Zhao, Zhiqiang
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (19) : 5330 - 5335
[7] 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
[8] Discovery of 2,4,6-trisubstituted N-arylsulfonyl piperidines as γ-secretase inhibitors
Li, Hongmei
Asberom, Theodros
Bara, Thomas A.
Clader, John W.
Greenlee, William J.
Josien, Hubert B.
McBriar, Mark D.
Nomeir, Amin
Pissarnitski, Dmitri A.
Rajagopalan, Murali
Xu, Ruo
Zhao, Zhiqiang
Song, Lixin
Zhang, Lili
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (22) : 6290 - 6294
[9] A practical approach to the synthesis of 2,4-disubstituted oxazoles from amino acids
Morwick, T
Hrapchak, M
DeTuri, M
Campbell, S
[J]. ORGANIC LETTERS, 2002, 4 (16) : 2665 - 2668
[10] 2,6-Disubstituted N-arylsulfonyl piperidines as γ-secretase inhibitors
Pissarnitski, Dmitri A.
Asberom, Theodros
Bara, Thomas A.
Buevich, Alex V.
Clader, John W.
Greenlee, William J.
Guzik, Henry S.
Josien, Hubert B.
Li, Wei
McEwan, Michael
McKittrick, Brian A.
Nechuta, Terry L.
Parker, Eric M.
Sinning, Lisa
Smith, Elizabeth M.
Song, Lixin
Vaccaro, Henry A.
Voigt, Johannes H.
Zhang, Lili
Zhang, Qi
Zhao, Zhiqiang
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (01) : 57 - 62

← 1 2 →