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

共 50 条

[21] Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1
Hosen, S. M. Zahid
Rubayed, Maruf
Dash, Raju
Junaid, Md
Mitra, Sarmistha
Alam, Muhammad Shaiful
Dey, Rupantar
CURRENT PHARMACEUTICAL DESIGN, 2018, 24 (33) : 3972 - 3979
[22] Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization
Cumming, Jared
Babu, Suresh
Huang, Ying
Carrol, Carolyn
Chen, Xia
Favreau, Leonard
Greenlee, William
Guo, Tao
Kennedy, Matthew
Kuvelkar, Reshma
Le, Thuy
Li, Guoqing
McHugh, Nansie
Orth, Peter
Ozgur, Lynne
Parker, Eric
Saionz, Kurt
Stamford, Andrew
Strickland, Corey
Tadesse, Dawit
Voigt, Johannes
Zhang, Lili
Zhang, Qi
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (09) : 2837 - 2842
[23] Structure-Based Survey of the Binding Modes of BACE1 Inhibitors
Hu, Hangchen
Chen, Zhaoqiang
Xu, Xiang
Xuo, Yechun
ACS CHEMICAL NEUROSCIENCE, 2019, 10 (02): : 880 - 889
[24] Iminoheterocycle as a druggable motif: BACE1 inhibitors and beyond
Zhu, Zhaoning
TRENDS IN PHARMACOLOGICAL SCIENCES, 2012, 33 (05) : 233 - 240
[25] Pyridinyl aminohydantoins as small molecule BACE1 inhibitors
Zhou, Ping
Li, Yanfang
Fan, Yi
Wang, Zheng
Chopra, Rajiv
Olland, Andrea
Hu, Yun
Magolda, Ronald L.
Pangalos, Menelas
Reinhart, Peter H.
Turner, M. James
Bard, Jonathan
Malamas, Michael S.
Robichaud, Albert J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (07) : 2326 - 2329
[26] Development of BACE1 inhibitors for Alzheimer's disease
Guo, Tao
Hobbs, Doug W.
CURRENT MEDICINAL CHEMISTRY, 2006, 13 (15) : 1811 - 1829
[27] Peptidomimetic Modulators of BACE1
Juliano, John Paul
Small, David H.
Aguilar, Marie-Isabel
AUSTRALIAN JOURNAL OF CHEMISTRY, 2020, 73 (04) : 366 - 376
[28] Characterization of Cerebrospinal Fluid BACE1 Species
Lopez-Font, Inmaculada
Boix, Claudia P.
Zetterberg, Henrik
Blennow, Kaj
Saez-Valero, Javier
MOLECULAR NEUROBIOLOGY, 2019, 56 (12) : 8603 - 8616
[29] Boom in the Development of Non-Peptidic β-Secretase (BACE1) Inhibitors for the Treatment of Alzheimer Disease
Silvestri, Romano
MEDICINAL RESEARCH REVIEWS, 2009, 29 (02) : 295 - 338
[30] BACE1: A Key Regulator in Alzheimer's Disease Progression and Current Development of its Inhibitors
Patel, Smith
Bansoad, Ankush Vardhaman
Singh, Rakesh
Khatik, Gopal L.
CURRENT NEUROPHARMACOLOGY, 2022, 20 (06) : 1174 - 1193

← 1 2 3 4 5 →