Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796):: A γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer's disease

被引：25

作者：

Prasad, C. V. C.

Zheng, Ming

Vig, Shikha

Bergstrom, Carl

Smith, David W.

Gao, Qi

Yeola, Suresh

Polson, Craig T.

Corsa, Jason A.

Guss, Valerie L.

Loo, Alice

Wang, Jian

Sleczka, Bogdan G.

Dangler, Charles

Robertson, Barbara J.

Hendrick, Joseph P.

Roberts, Susan B.

Barten, Donna M.

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Discovery Chem, Wallingford, CT 06492 USA

[2] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Drug Metab & Pharmacokinet, Wallingford, CT 06492 USA

[3] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Analyt R&D, Wallingford, CT 06492 USA

[4] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Neurosci Biol, Wallingford, CT 06492 USA

[5] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Exploratory Toxicol, Wallingford, CT 06492 USA

[6] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Bioanalyt Res, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 14期

关键词：

gamma-sectretase inhibitors;

D O I：

10.1016/j.bmcl.2007.04.082

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report on the design of benzodiazepin ones as peptidomimetics at the carboxy terminus of hydroxyamides. structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to AP reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：4006 / 4011

页数：6

共 30 条

[11]

Klein William L, 2006, Alzheimers Dement, V2, P43, DOI 10.1016/j.jalz.2005.11.003

[12] Concentration-dependent modulation of amyloid-β in vivo and in vitro using the γ-secretase inhibitor, LY-450139 [J].

Lanz, Thomas A. ;

Karmilowicz, Michael J. ;

Wood, Kathleen M. ;

Pozdnyakov, Nikolay ;

Du, Ping ;

Piotrowski, Mary A. ;

Brown, Tracy M. ;

Nolan, Charles E. ;

Richter, Karl E. G. ;

Finley, James E. ;

Fei, Qing ;

Ebbinghaus, Charles F. ;

Chen, Yuhpyng L. ;

Spracklin, Douglas K. ;

Tate, Barbara ;

Geoghegan, Kieran F. ;

Lau, Lit-Fui ;

Auperin, David D. ;

Schachter, Joel B. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 319 (02) :924-933

[13] Notch signalling and the control of cell fate choices in vertebrates [J].

Lewis, J .

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 1998, 9 (06) :583-589

[14] A novel series of potent γ-secretase inhibitors based on a benzobicyclo[4.2.1]nonane core [J].

Lewis, SJ ;

Smith, AL ;

Neduvelil, JG ;

Stevenson, GI ;

Lindon, MJ ;

Jones, AB ;

Shearman, MS ;

Beher, D ;

Clarke, E ;

Best, JD ;

Peachey, JE ;

Harrison, T ;

Castro, JL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (02) :373-378

[15] Synthesis and γ-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres [J].

Nadin, A ;

Owens, AP ;

Castro, JL ;

Harrison, T ;

Shearman, MS .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (01) :37-41

[16]

NEITZEL M, 2005, Patent No. 04248

[17] 2,3-benzodiazepin-1,4-diones as peptidomimetic inhibitors of γ-secretase [J].

Prasad, CVC ;

Vig, S ;

Smith, DW ;

Gao, Q ;

Polson, CT ;

Corsa, JA ;

Guss, VL ;

Loo, A ;

Barten, DM ;

Zheng, M ;

Felsenstein, KM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (13) :3535-3538

[18] Hydroxytriamides as potent γ-secretase inhibitors [J].

Prasada, CVC ;

Noonan, JW ;

Sloan, CP ;

Lau, W ;

Vig, S ;

Parker, MF ;

Smith, DW ;

Hansel, SB ;

Polson, CT ;

Barten, DM ;

Felsenstein, KM ;

Roberts, SB .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (08) :1917-1921

[19] Fenchylamine sulfonamide inhibitors of amyloid β peptide production by the γ-secretase proteolytic pathway:: Potential small-molecule therapeutic agents for the treatment of Alzheimer's disease [J].

Rishton, GM ;

Retz, DM ;

Tempest, PA ;

Novotny, J ;

Kahn, S ;

Treanor, JJS ;

Lile, JD ;

Citron, M .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (12) :2297-2299

[20]

Rosen L.B., 2006, ALZHEIMERS DEMEN, V2, P79

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