Novel heterocyclic-substituted benzofuran histamine H3 receptor antagonists:: In vitro properties, drug-likeness, and behavioral activity

被引：29

作者：

Cowart, Marion ^{[1
]}

Gfesser, Gregory A. ^{[1
]}

Browman, Kaitlin E. ^{[1
]}

Faghih, Ramin ^{[1
]}

Miller, Thomas R. ^{[1
]}

Milicic, Ivan ^{[1
]}

Baranowski, John L. ^{[1
]}

Krueger, Kathleen M. ^{[1
]}

Witte, David G. ^{[1
]}

Molesky, Angela L. ^{[1
]}

Komater, Victoria A. ^{[1
]}

Buckley, Michael J. ^{[1
]}

Diaz, Gilbert J. ^{[1
]}

Gagne, Gerard D. ^{[1
]}

Zhou, Deliang ^{[1
]}

Deng, Xiaoqing ^{[1
]}

Pan, Liping ^{[1
]}

Roberts, Ellen M. ^{[1
]}

Diehl, Marilyn S. ^{[1
]}

Wetter, Jill M. ^{[1
]}

Marsh, Kennan C. ^{[1
]}

Fox, Gerard B. ^{[1
]}

Brioni, Jorge D. ^{[1
]}

Esbenshade, Timothy A. ^{[1
]}

Hancock, Arthur A. ^{[1
]}

机构：

[1] Abbott Labs, Dept Neurosci Res, Abbott Pk, IL 60064 USA

来源：

BIOCHEMICAL PHARMACOLOGY | 2007年 / 73卷 / 08期

关键词：

histamine; H-3; receptor; antagonist; CNS; A-688057;

D O I：

10.1016/j.bcp.2007.02.010

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H-3 receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H-3 receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H-3 receptors (H-3, K-i = 13 nM) versus off-target receptors and channels (including the hERG K+ channel, K-i > 9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4) = 2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP450 inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9 h, 1.7 h in dog, 1.8 h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound. (c) 2007 Elsevier Inc. All rights reserved.

引用

页码：1243 / 1255

页数：13

共 52 条

[51]

Yates SL, 1999, J PHARMACOL EXP THER, V289, P1151

[52] Lack of cataleptogenic potentiation with non-imidazole H3 receptor antagonists reveals potential drug-drug interactions between imidazole-based H3 receptor antagonists and antipsychotic drugs [J].

Zhang, M ;

Ballard, ME ;

Pan, LP ;

Roberts, S ;

Faghih, R ;

Cowart, M ;

Esbenshade, TA ;

Fox, GB ;

Decker, MW ;

Hancock, AA ;

Rueter, LE .

BRAIN RESEARCH, 2005, 1045 (1-2) :142-149

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