Selective GlyT1 Inhibitors: Discovery of [4-(3-Fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a Promising Novel Medicine To Treat Schizophrenia

被引：116

作者：

Pinard, Emmanuel ^{[1
]}

Alanine, Alexander ^{[1
]}

Alberati, Daniela ^{[1
]}

Bender, Markus ^{[1
]}

Borroni, Edilio ^{[1
]}

Bourdeaux, Patrick ^{[1
]}

Brom, Virginie ^{[1
]}

Burner, Serge ^{[1
]}

Fischer, Holger ^{[1
]}

Hainzl, Dominik ^{[1
]}

Halm, Remy ^{[1
]}

Hauser, Nicole ^{[1
]}

Jolidon, Synese ^{[1
]}

Lengyel, Judith ^{[1
]}

Marty, Hans-Peter ^{[1
]}

Meyer, Thierry ^{[1
]}

Moreau, Jean-Luc ^{[1
]}

Mory, Roland ^{[1
]}

Narquizian, Robert ^{[1
]}

Nettekoven, Mathias ^{[1
]}

Norcross, Roger D. ^{[1
]}

Puellmann, Bernd ^{[1
]}

Schmid, Philipp ^{[1
]}

Schmitt, Sebastien ^{[1
]}

Stalder, Henri ^{[1
]}

Wermuth, Roger ^{[1
]}

Wettstein, Joseph G. ^{[1
]}

Zimmerli, Daniel ^{[1
]}

机构：

[1] F Hoffmann La Roche & Co Ltd, Div Pharmaceut, CH-4070 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 12期

关键词：

GLYCINE TRANSPORTER TYPE-1; D-ASPARTATE RECEPTORS; SUBSTITUTED SPIROPIPERIDINES; POTENT; DESIGN; SITE; SAR;

D O I：

10.1021/jm100210p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.

引用

页码：4603 / 4614

页数：12

共 50 条

[1] Novel 5-fluoro-6-(4-(2-fluorophenyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-benzo[d]imidazole Derivatives as Promising Urease Inhibitors
Moghadam, Ebrahim Saeedian
Al-Sadi, Abdullah Mohammed
Talebi, Meysam
Amanlou, Massoud
Stoll, Raphael
Amini, Mohsen
Abdel-Jalil, Raid
LETTERS IN DRUG DESIGN & DISCOVERY, 2024, 21 (02) : 297 - 304
[2] Radiosynthesis of [5-[11C]methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-2-yl]-methanone ([11C]RO5013853), a novel PET tracer for the glycine transporter type I (GlyT1)
Pinard, Emmanuel
Burner, Serge
Cueni, Philipp
Hartung, Thomas
Norcross, Roger D.
Schmid, Philipp
Waldmeier, Pius
Zielinski, Guy
Ravert, Hayden T.
Holt, Daniel P.
Dannals, Robert F.
JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 2011, 54 (11): : 702 - 707
[3] Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl) ethyl)isobenzofuran-1(3H)-one
Tang, Haifeng
de Jesus, Reynald K.
Walsh, Shawn P.
Zhu, Yuping
Yan, Yan
Priest, Birgit T.
Swensen, Andrew M.
Alonso-Galicia, Magdalena
Felix, John P.
Brochu, Richard M.
Bailey, Timothy
Thomas-Fowlkes, Brande
Zhou, Xiaoyan
Pai, Lee-Yuh
Hampton, Caryn
Hernandez, Melba
Owens, Karen
Roy, Sophie
Kaczorowski, Gregory J.
Yang, Lihu
Garcia, Maria L.
Pasternak, Alexander
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (21) : 5829 - 5832
[4] Metabolism, Excretion, and Pharmacokinetics of ((3,3-Difluoropyrrolidin-1-yl)((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a Dipeptidyl Peptidase Inhibitor, in Rat, Dog and Human
Sharma, Raman
Sun, Hao
Piotrowski, David W.
Ryder, Tim F.
Doran, Shawn D.
Dai, Haiqing
Prakash, Chandra
DRUG METABOLISM AND DISPOSITION, 2012, 40 (11) : 2143 - 2161
[5] 2-phenyl-4(5)-[[4-(pyrimidin-2-yl)piperazin-1-yl]methyl]imidazole. A highly selective antagonist at cloned human D-4 receptors
Thurkauf, A
Yuan, J
Chen, X
He, XS
Wasley, JWF
Hutchison, A
Woodruff, KH
Meade, R
Hoffman, DC
Donovan, H
JonesHertzog, DK
JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (01) : 1 - 3
[6] 2-phenyl-4(5)-(1-[4-(pyrimidin-2-yl)piperazin-1-yl]) methyl imidazole and related compounds as selective antagonists at cloned human D4 receptors.
Thurkauf, A
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1997, 213 : 159 - MEDI
[7] Synthesis and preliminary in vivo evaluation of 4[18F]fluoro-N-{2-[4-(6-trifluoromethylpyridin-2-yl) piperazin-1-yl]ethyl}benzamide, a potential PET radioligand for the 5-HT1A receptor
Vandecapelle, M
Dumont, F
De Vos, F
Strijckmans, K
Leysen, D
Audenaert, K
Dierckx, RA
Slegers, G
JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 2004, 47 (09): : 531 - 542
[8] 1-(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-5-yl)-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethanone
Zhi, Shuang
Zheng, Guo
Liu, Ying
Liu, Deng-Ke
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2012, 68 : O1293 - +
[9] Pharmacological evaluation of novel (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives as TRPV4 antagonists for the treatment of pain
Tsuno, Naoki
Yukimasa, Akira
Yoshida, Osamu
Suzuki, Shinji
Nakai, Hiromi
Ogawa, Tomoyuki
Fujiu, Motohiro
Takaya, Kenji
Nozu, Azusa
Yamaguchi, Hiroki
Matsuda, Hidetoshi
Funaki, Satoko
Yamanada, Natsue
Tanimura, Miki
Nagamatsu, Daiki
Asaki, Toshiyuki
Horita, Narumi
Yamamoto, Miyuki
Hinata, Mikie
Soga, Masahiko
Imai, Masayuki
Morioka, Yasuhide
Kanemasa, Toshiyuki
Sakaguchi, Gaku
Iso, Yasuyoshi
BIOORGANIC & MEDICINAL CHEMISTRY, 2017, 25 (07) : 2177 - 2190
[10] (S)-3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2-(piperazin-1-yl)propanoic acid compounds: Synthesis and biological evaluation of dual PPARα/γ agonists
Zhou, Xinbo
Chen, Wei
Xu, Cheng
Fan, Shiyong
Xie, Yunde
Zhong, Wu
Wang, Lili
Li, Song
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (08) : 2605 - 2608

← 1 2 3 4 5 →