The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists

被引：18

作者：

Johnson, Dale J. ^{[1
]}

Forbes, Ian T. ^{[1
]}

Watson, Steve P. ^{[1
]}

Garzya, Vincenzo ^{[1
]}

Stevenson, Graeme I. ^{[1
]}

Walker, Graham R. ^{[1
]}

Mudhar, Harminder S. ^{[1
]}

Flynn, Sean T. ^{[1
]}

Wyman, Paul A. ^{[1
]}

Smith, Paul W. ^{[1
]}

Murkitt, Graham S. ^{[1
]}

Lucas, Adam J. ^{[1
]}

Mookherjee, Claudette R. ^{[1
]}

Watson, Jeannette M. ^{[1
]}

Gartlon, Jane E. ^{[1
]}

Bradford, Andrea M. ^{[1
]}

Brown, Fiona ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Harlow CM19 5AW, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 18期

关键词：

Muscarinic M-1 agonist; Cognitive enhancer; Allosteric; Central nervous system penetration; Benzoxazolinone; Oxidole; ALLOSTERIC AGONIST; RECEPTOR SUBTYPES; P-GLYCOPROTEIN; PHARMACOLOGY; DISEASE;

D O I：

10.1016/j.bmcl.2010.07.097

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M-1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5434 / 5438

页数：5

共 27 条

[1] Discovery of Novel N-Substituted Oxindoles as Selective M1 and M4 Muscarinic Acetylcholine Receptors Partial Agonists
Sumiyoshi, Takaaki
Enomoto, Takeshi
Takai, Kentaro
Takahashi, Yoko
Konishi, Yasuko
Uruno, Yoshiharu
Tojo, Kengo
Suwa, Atsushi
Matsuda, Harumi
Nakako, Tomokazu
Sakai, Mutsuko
Kitamura, Atsushi
Uematsu, Yasuaki
Kiyoshi, Akihiko
ACS MEDICINAL CHEMISTRY LETTERS, 2013, 4 (02): : 244 - 248
[2] Drug discovery of novel N-substituted oxindoles as potent and high selective muscarinic M1 and M4 receptor partial agonist
Takai, Kentaro
Sumiyoshi, Takaaki
Uruno, Yoshiharu
Tojo, Kengo
Suwa, Atsushi
Takahashi, Yoko
Konishi, Yasuko
Enomoto, Takeshi
Matsuda, Harumi
Sakai, Mutsuko
Nakako, Tomokazu
Kiyoshi, Akihiko
Uematsu, Yasuaki
Kitamura, Atsushi
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2013, 245
[3] Discovery of N-substituted 7-azaindoline derivatives as potent, orally available M1 and M4 muscarinic acetylcholine receptors selective agonists
Takai, Kentaro
Inoue, Yasunao
Konishi, Yasuko
Suwa, Atsushi
Uruno, Yoshiharu
Matsuda, Harumi
Nakako, Tomokazu
Sakai, Mutsuko
Nishikawa, Hiroyuki
Hashimoto, Gakuji
Enomoto, Takeshi
Kitamura, Atsushi
Uematsu, Yasuaki
Kiyoshi, Akihiko
Sumiyoshi, Takaaki
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (14) : 3189 - 3193
[4] Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists
Budzik, Brian
Garzya, Vincenzo
Shi, Dongchuan
Walker, Graham
Woolley-Roberts, Marie
Pardoe, Joanne
Lucas, Adam
Tehan, Ben
Rivero, Ralph A.
Langmead, Christopher J.
Watson, Jeannette
Wu, Zining
Forbes, Ian T.
Jin, Jian
ACS MEDICINAL CHEMISTRY LETTERS, 2010, 1 (06): : 244 - 248
[5] Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M1 and M4 muscarinic acetylcholine receptors agonists
Uruno, Yoshiharu
Konishi, Yasuko
Suwa, Atsushi
Takai, Kentaro
Tojo, Kengo
Nakako, Tomokazu
Sakai, Mutsuko
Enomoto, Takeshi
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Kitamura, Atsushi
Sumiyoshi, Takaaki
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (22) : 5357 - 5361
[6] Identification of N-substituted 8-azatetrahydroquinolone derivatives as selective and orally active M1 and M4 muscarinic acetylcholine receptors agonists
Takai, Kentaro
Inoue, Yasunao
Konishi, Yasuko
Suwa, Atsushi
Uruno, Yoshiharu
Matsuda, Harumi
Nakako, Tomokazu
Sakai, Mutsuko
Nishikawa, Hiroyuki
Hashimoto, Gakuji
Enomoto, Takeshi
Kitamura, Atsushi
Uematsu, Yasuaki
Kiyoshi, Akihiko
Sumiyoshi, Takaaki
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (16) : 4644 - 4647
[7] Synthesis of furanyl and oxazolyl N-substituted piperidine and imidazoline salts as potential Agonists of M1 muscarinic receptors
Aguado, Andreina
Boulos, John
Carreras, Anladys
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Rodriquez, Judith
JOURNAL OF HETEROCYCLIC CHEMISTRY, 2007, 44 (06) : 1517 - 1520
[8] Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M1 agonists
Liu, Bin
Croy, Carrie H.
Hitchcock, Stephen A.
Allen, Jennifer R.
Rao, Zhigang
Evans, David
Bures, Mark G.
McKinzie, David L.
Watt, Marla Leigh
Gregory, G. Stuart
Hansen, Marvin M.
Hoogestraat, Paul J.
Jamison, James A.
Okha-Mokube, Fese M.
Stratford, Robert E.
Turner, William
Bymaster, Frank
Felder, Christian C.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (19) : 4158 - 4163
[9] A Stereoselective Synthesis of a 3,4,5-Substituted Piperidine of Interest as a Selective Muscarinic (M1) Receptor Agonist
Broadley, Kenneth J.
Buffat, Maxime G. P.
Davies, Robin H.
Thomas, Eric J.
SYNLETT, 2016, 27 (01) : 45 - 50
[10] Drug discovery and large-scale synthesis for 7-azaindoline derivatives as potent, orally available, selective M1 and M4 muscarinic acetylcholine receptors agonists
Uruno, Yoshiharu
Inoue, Yasunao
Konishi, Yasuko
Suwa, Atsushi
Takai, Kentaro
Hashimoto, Kazuki
Matsuda, Harumi
Nakako, Tomokazu
Sakai, Mutsuko
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Kiyoshi, Akihiko
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ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2015, 249

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