Carbazole-containing arylcarboxamides as BACE1 inhibitors

被引：25

作者：

Bertini, Simone ^{[1
]}

Asso, Valentina ^{[1
]}

Ghilardi, Elisa ^{[1
]}

Granchi, Carlotta ^{[1
]}

Manera, Clementina ^{[1
]}

Minutolo, Filippo ^{[1
]}

Saccomanni, Giuseppe ^{[1
]}

Bortolato, Andrea ^{[2
]}

Mason, Jonathan ^{[2
,4
]}

Moro, Stefano ^{[3
]}

Macchia, Marco ^{[1
]}

机构：

[1] Univ Pisa, Dipartimento Sci Farmaceut, I-56126 Pisa, Italy

[2] Heptares Therapeut Ltd, Welwyn Garden City AL7 RAX, Herts, England

[3] Univ Padua, Dipartimento Sci Farmaceut, Mol Modeling Sect, I-35131 Padua, Italy

[4] Lundbeck AS, DK-2500 Copenhagen, Denmark

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 22期

关键词：

Alzheimer; BACE1; Carbazole; Molecular docking; Flap; AMYLOID PRECURSOR PROTEIN; BETA-SECRETASE; ALZHEIMERS-DISEASE; CRYSTAL-STRUCTURE; DESIGN; MODEL; SITE; MATURATION; PREDICTION; DOCKING;

D O I：

10.1016/j.bmcl.2011.09.064

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

beta-Secretase (BACE1) is widely recognized as a prime drug target for the treatment of Alzheimer's disease (AD). In this Letter, we report the synthesis and the BACE1 inhibitory activity of novel, variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylcarboxamides. The best results have been obtained with the introduction of a 4-OMe substituent (IC50 = 3.8 mu M) or a 3,4-dichloro substituent (IC50 = 2.5 mu M) in the amidic aromatic ring. The blood-brain barrier penetration predictions resulted to be promising for this type of compounds. To better understand the structure-activity relationships (SAR) of the new derivatives, a docking study procedure has been applied exploiting different conformational and ionic states of BACE1. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6657 / 6661

页数：5

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