Discovery of γ-secretase inhibitors efficacious in a transgenic animal model of Alzheimer's disease

被引：24

作者：

Asberom, Theodros

Zhao, Zhiqiang

Bara, Thomas A.

Clader, John W.

Greenlee, William J.

Hyde, Lynn A.

Josien, Hubert B.

Li, Wei

McPhail, Andrew T.

Nomeir, Amin A.

Parker, Eric M.

Rajagopalan, Murali

Song, Lixin

Wong, Gwendolyn T.

Zhang, Lili

Zhang, Qi

Pissarnitski, Dmitri A.

机构：

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

[2] Schering Plough Res Inst, Dept Cent Nervous Syst, Kenilworth, NJ 07033 USA

[3] Duke Univ, Dept Chem, Durham, NC 27708 USA

[4] Schering Plough Res Inst, Dept Drug Metab & Pharmacokinet, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 02期

关键词：

Alzheimer's disease; gamma-secretase inhibitors; Kulinkovich reaction;

D O I：

10.1016/j.bmcl.2006.10.011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce A beta levels in TgCRND8 mice after a single PO dosing at 30 mpk. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：511 / 516

页数：6

共 50 条

[31] Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease
Machauer, Rainer
Lueoend, Rainer
Hurth, Konstanze
Veenstra, Siem J.
Rueeger, Heinrich
Voegtle, Markus
Tintelnot-Blomley, Marina
Rondeau, Jean-Michel
Jacobson, Laura H.
Laue, Grit
Beltz, Karen
Neumann, Ulf
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (20) : 15262 - 15279
[32] Beta-secretase as a target for Alzheimer's disease drug discovery: an overview of in vitro methods for characterization of inhibitors
Mancini, Francesca
De Simone, Angela
Andrisano, Vincenza
ANALYTICAL AND BIOANALYTICAL CHEMISTRY, 2011, 400 (07) : 1979 - 1996
[33] Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and Efficacious γ-Secretase Inhibitors
Ye, Xiaocong M.
Konradi, Andrei W.
Smith, Jenifer
Xu, Ying-Zi
Dressen, Darren
Garofalo, Albert W.
Marugg, Jennifer
Sham, Hing L.
Truong, Anh P.
Jagodzinski, Jacek
Pleiss, Michael
Zhang, Hongbin
Goldbach, Erich
Sauer, John-Michael
Brigham, Elizabeth
Bova, Michael
Basi, Guriqbal S.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (07) : 2195 - 2199
[34] γ-Secretase in Alzheimer’s disease
Ji-Yeun Hur
Experimental & Molecular Medicine, 2022, 54 : 433 - 446
[35] Recent developments of structure based β-secretase inhibitors for Alzheimer's disease
Ghosh, AK
Kumaragurubaran, N
Tang, J
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (16) : 1609 - 1622
[36] γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes
Imbimbo, Bruno P.
Giardina, Giuseppe A. M.
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2011, 11 (12) : 1555 - 1570
[37] Secretase inhibitors for the treatment of Alzheimer's disease: Long road ahead
Kumar, Devendra
Ganeshpurkar, Ankit
Kumar, Dileep
Modi, Gyan
Gupta, Sanjeev Kumar
Singh, Sushil Kumar
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 148 : 436 - 452
[38] BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease
Ghosh, Arun K.
Osswald, Heather L.
CHEMICAL SOCIETY REVIEWS, 2014, 43 (19) : 6765 - 6813
[39] In Silico Design of Beta-Secretase Inhibitors in Alzheimer's Disease
Semighini, Evandro Pizeta
CHEMICAL BIOLOGY & DRUG DESIGN, 2015, 86 (03) : 284 - 290
[40] Disease-Modifying Approach to the Treatment of Alzheimer's Disease From α-Secretase Activators to γ-Secretase Inhibitors and Modulators
Panza, Francesco
Solfrizzi, Vincenzo
Frisardi, Vincenza
Capurso, Cristiano
D'Introno, Alessia
Colacicco, Anna M.
Vendemiale, Gianluigi
Capurso, Antonio
Imbimbo, Bruno P.
DRUGS & AGING, 2009, 26 (07) : 537 - 555

← 1 2 3 4 5 →