Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M1 and M4 muscarinic acetylcholine receptors agonists

被引：15

作者：

Uruno, Yoshiharu ^{[1
]}

Konishi, Yasuko ^{[1
]}

Suwa, Atsushi ^{[1
]}

Takai, Kentaro ^{[2
]}

Tojo, Kengo ^{[1
]}

Nakako, Tomokazu ^{[2
]}

Sakai, Mutsuko ^{[1
]}

Enomoto, Takeshi ^{[2
]}

Matsuda, Harumi ^{[2
]}

Kitamura, Atsushi ^{[2
]}

Sumiyoshi, Takaaki ^{[1
]}

机构：

[1] Sumitomo Dainippon Pharma Co Ltd, Drug Res Div, Konohana Ku, Osaka 5540022, Japan

[2] Sumitomo Dainippon Pharma Co Ltd, Drug Res Div, Suita, Osaka 5640053, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 22期

基金：

日本学术振兴会;

关键词：

Muscarinic acetylcholine receptors; M-1 muscarinic acetylcholine receptor; M-4 muscarinic acetylcholine receptor; Partial agonist; Antipsychotic agent; Dihydroquinazolinone derivatives; MICE LACKING; PHARMACOLOGY; XANOMELINE;

D O I：

10.1016/j.bmcl.2015.09.032

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We designed and synthesized a series of dihydroquinazolinone derivatives as selective M-1 and M-4 muscarinic acetylcholine receptors agonists. Introduction of the N-carbethoxy piperidine unit into a HTS hit compound followed by optimization of the amine linker and the carbamoyl moiety led to the identification of compound 1 as a potential candidate. The identified compound 1 showed high selectivity for M-1 and M-4 muscarinic acetylcholine receptors with M-4 partial agonistic activity. In addition, compound 1 showed good brain penetration and reversed methamphetamine-induced hyperlocomotion in rats (ED50 = 3.0 mg/kg, sc). (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5357 / 5361

页数：5

共 50 条

[1] 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
[2] 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
[3] 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
Hashimoto, Gakuji
Enomoto, Takeshi
Kitamura, Atsushi
Uematsu, Yasuaki
Kiyoshi, Akihiko
Sumiyoshi, Takaaki
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2015, 249
[4] Crystal structures of the M1 and M4 muscarinic acetylcholine receptors
David M. Thal
Bingfa Sun
Dan Feng
Vindhya Nawaratne
Katie Leach
Christian C. Felder
Mark G. Bures
David A. Evans
William I. Weis
Priti Bachhawat
Tong Sun Kobilka
Patrick M. Sexton
Brian K. Kobilka
Arthur Christopoulos
Nature, 2016, 531 : 335 - 340
[5] Crystal structures of the M1 and M4 muscarinic acetylcholine receptors
Thal, David M.
Sun, Bingfa
Feng, Dan
Nawaratne, Vindhya
Leach, Katie
Felder, Christian C.
Bures, Mark G.
Evans, David A.
Weis, William I.
Bachhawat, Priti
Kobilka, Tong Sun
Sexton, Patrick M.
Kobilka, Brian K.
Hristopoulos, Arthur C.
NATURE, 2016, 531 (7594) : 335 - +
[6] Interaction of anandamide with the M1 and M4 muscarinic acetylcholine receptors
Christopoulos, A
Wilson, K
BRAIN RESEARCH, 2001, 915 (01) : 70 - 78
[7] Discovery of potent, selective, CNS-penetrant potentiators of glycine receptors
DiMauro, Erin
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2016, 252
[8] Process Development for the Synthesis of a Selective M1 and M4 Muscarinic Acetylcholine Receptors Agonist
Uruno, Yoshiharu
Hashimoto, Kazuki
Hiyama, Yoichi
Sumiyoshi, Takaaki
ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2017, 21 (10) : 1610 - 1615
[9] 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
[10] 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

← 1 2 3 4 5 →