Pharmacophore-based search, synthesis, and biological evaluation of anthranilic amides as novel blockers of the Kv1.5 channel

被引：44

作者：

Peukert, S ^{[1
]}

Brendel, J ^{[1
]}

Pirard, B ^{[1
]}

Strübing, C ^{[1
]}

Kleemann, HW ^{[1
]}

Böhme, T ^{[1
]}

Hemmerle, H ^{[1
]}

机构：

[1] Aventis Pharma Deutschland GmbH, Med Chem & DG Cardiovasc, D-65926 Frankfurt, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 11期

关键词：

Kv1.5; blockers; anthranilic amides; atrial fibrillation;

D O I：

10.1016/j.bmcl.2004.03.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The search for novel, potent Kv1.5 blockers based on an anthranilic amide scaffold employing a pharmacophore-based virtual screening approach is described. The synthesis and structure-activity relationships (SAR) with respect to inhibition of the Kv1.5 channel are discussed. The most potent compounds display sub-micromolar inhibition of Kv1.5 and no significant effect on the HERG channel. In addition, good oral bioavailability is demonstrated for compound X in rats. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：2823 / 2827

页数：5

共 45 条

[1] Pharmacophore Mapping for Kv1.5 Potassium Channel Blockers
Yang, Qian
Du, Lupei
Tsai, Keng-Chang
Wang, Xiaojian
Li, Minyong
You, Qidong
QSAR & COMBINATORIAL SCIENCE, 2009, 28 (01): : 59 - 71
[2] Design, synthesis, and biological evaluation of arylmethylpiperidines as Kv1.5 potassium channel inhibitors
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Yang, Qian
Tang, Yiqun
You, Qidong
Guo, Xiaoke
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2022, 37 (01) : 462 - 471
[3] Identification, synthesis, and activity of novel blockers of the voltage-gated potassium channel kv1.5
Peukert, S
Brendel, J
Pirard, B
Brüggemann, A
Below, P
Kleemann, HW
Hemmerle, H
Schmidt, W
JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (04) : 486 - 498
[4] Identification, synthesis, and biological evaluation of two novel classes of Kv1.5 inhibitors
Peukert, S
Brendel, J
Pirard, B
Kleemann, HW
Boehme, T
Below, P
Struebing, C
Wirth, K
Goegelein, H
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2004, 227 : U6 - U6
[5] Synthesis and evaluation of diphenylphosphinic amides and diphenylphosphine oxides as inhibitors of Kv1.5
Olsson, Roine I.
Jacobson, Ingemar
Bostrom, Jonas
Fex, Tomas
Bjore, Annika
Olsson, Christina
Sundell, Johan
Gran, Ulrik
Ohrn, Anna
Nordin, Andreas
Gyll, Jonna
Thorstensson, Maria
Hayen, Ahlke
Aplander, Karolina
Hidestal, Olle
Jiang, Fanyi
Linhardt, Gunilla
Forsstrom, Elin
Collins, Teresa
Sundqvist, Monika
Lindhardt, Emma
Astrand, Annika
Lofberg, Boel
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (03) : 706 - 710
[6] Structure-Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of KV1.5 Channel Blockers
Yang, Qian
Fedida, David
Xu, Hongjian
Wang, Binghe
Du, Lupei
Wang, Xiaojian
Li, Minyong
You, Qidong
CHEMMEDCHEM, 2010, 5 (08) : 1353 - 1358
[7] Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening
Ramirez, David
Concha, Guierdy
Arevalo, Barbara
Prent-Penaloza, Luis
Zuniga, Leandro
Kiper, Aytug K.
Rinne, Susanne
Reyes-Parada, Miguel
Decher, Niels
Gonzalez, Wendy
Caballero, Julio
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (16)
[8] Pharmacophore-Based Drug Design and Biological Evaluation of Novel ABCB1 Inhibitors
Zhang, Sheng-lie
Wei, Yin-xiang
Li, Qian
Sun, Hao-peng
Peng, Hui
You, Qi-dong
CHEMICAL BIOLOGY & DRUG DESIGN, 2013, 81 (03) : 349 - 358
[9] Electrophysiological effects of novel Kv1.5 channel blockers on left versus right pig atrium in comparison with lKr-blockade
Wirth, KJ
Brendel, J
Busch, AE
Knobloch, K
EUROPEAN HEART JOURNAL, 2002, 23 : 39 - 39
[10] Pharmacophore-based identification of novel hERG channel blockers of natural origin - Development of a virtual screening workflow and experimental validation
Kratz, J. M.
Edtbauer, M.
Mair, C. E.
Hering, S.
Schuster, D.
Rollinger, J. M.
PLANTA MEDICA, 2013, 79 (13) : 1113 - 1113

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