Design and Synthesis of 4-Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

被引：17

作者：

Liu, Shuang ^{[1
]}

Zha, Congxiang ^{[1
]}

Nacro, Kassoum ^{[1
]}

Hu, Min ^{[1
]}

Cui, Wenge ^{[1
]}

Yang, Yuh-Lin ^{[1
]}

Bhatt, Ulhas ^{[1
]}

Sambandam, Aruna ^{[1
]}

Isherwood, Matthew ^{[1
]}

Yet, Larry ^{[1
]}

Herr, Michael T. ^{[1
]}

Ebeltoft, Sarah ^{[1
]}

Hassler, Carla ^{[1
]}

Fleming, Linda ^{[1
]}

Pechulis, Anthony D. ^{[1
]}

Payen-Fornicola, Anne ^{[1
]}

Holman, Nicholas ^{[1
]}

Milanowski, Dennis ^{[1
]}

Cotterill, Ian ^{[1
]}

Mozhaev, Vadim ^{[1
]}

Khmelnitsky, Yuri ^{[1
]}

Guzzo, Peter R. ^{[1
]}

Sargent, Bruce J. ^{[1
]}

Molino, Bruce F. ^{[1
]}

Olson, Richard ^{[2
]}

King, Dalton ^{[2
]}

Lelas, Snjezana ^{[2
]}

Li, Yu-Wen ^{[2
]}

Johnson, Kim ^{[2
]}

Molski, Thaddeus ^{[2
]}

One, Anitra ^{[2
]}

Ng, Alicia ^{[2
]}

Haskell, Roy ^{[2
]}

Clarke, Wendy ^{[2
]}

Bertekap, Robert ^{[2
]}

O'Connell, Jonathan ^{[2
]}

Lodge, Nicholas ^{[2
]}

Sinz, Michael ^{[2
]}

Adams, Stephen ^{[2
]}

Zaczek, Robert ^{[2
]}

Macor, John E. ^{[2
]}

机构：

[1] AMRI, Albany, NY 12212 USA

[2] Bristol Myers Squibb R&D, Wallingford, CT 06492 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 07期

关键词：

Triple reuptake inhibitor; TRI; serotonin reuptake inhibitor; dopamine reuptake inhibitor; norepinephrine reuptake inhibitor; depression; antidepressant; DOPAMINE; NOREPINEPHRINE; DEPRESSION; OCCUPANCY; MECHANISM; SSRIS;

D O I：

10.1021/ml500053b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

引用

页码：760 / 765

页数：6

共 50 条

[21] Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors
Song, Gaopeng
Zhu, Xiang
Li, Junhua
Hu, Dekun
Zhao, Dongsheng
Liao, Yixian
Lin, Juntong
Zhang, Lian-Hui
Cui, Zi-Ning
BIOORGANIC & MEDICINAL CHEMISTRY, 2017, 25 (20) : 5709 - 5717
[22] 1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane: Further insights into a class of triple re-uptake inhibitors
Micheli, Fabrizio
Cavanni, Paolo
Bettati, Michela
Bonanomi, Giorgio
Di Fabio, Romano
Fazzolari, Elettra
Marchioro, Carla
Roscic, Maja
Tarsi, Luca
Visentini, Filippo
Zonzini, Laura
Worby, Angela
BIOORGANIC & MEDICINAL CHEMISTRY, 2011, 19 (11) : 3451 - 3461
[23] 4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design, synthesis and structure-activity relationships
Fish, Paul V.
Andrews, Mark D.
Fray, M. Jonathan
Stobie, Alan
Wakenhut, Florian
Whitlock, Gavin A.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (10) : 2829 - 2834
[24] Design, Synthesis, and Functional Evaluation of 1, 5-Disubstituted Tetrazoles as Monoamine Neurotransmitter Reuptake Inhibitors
Paudel, Suresh
Wang, Shuji
Kim, Eunae
Kundu, Dooti
Min, Xiao
Shin, Chan Young
Kim, Kyeong-Man
BIOMOLECULES & THERAPEUTICS, 2022, 30 (02) : 191 - 202
[25] Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols
Kim, Callain Y.
Mahaney, Paige E.
McConnell, Oliver
Zhang, Yingru
Manas, Eric
Ho, Douglas M.
Deecher, Darlene C.
Trybulski, Eugene J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (17) : 5029 - 5032
[26] 1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Triple Reuptake Inhibitors
Micheli, Fabrizio
Cavanni, Paolo
Arban, Roberto
Benedetti, Roberto
Bertani, Barbara
Bettati, Michela
Bettelini, Letizia
Bonanomi, Giorgio
Braggio, Simone
Checchia, Anna
Davalli, Silvia
Di Fabio, Romano
Fazzolari, Elettra
Fontana, Stefano
Marchioro, Carla
Minick, Doug
Negri, Michele
Oliosi, Beatrice
Read, Kevin D.
Sartori, Ilaria
Tedesco, Giovanna
Tarsi, Luca
Terreni, Silvia
Visentini, Filippo
Zocchi, Alessandro
Zonzini, Laura
JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (06) : 2534 - 2551
[27] Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors-Part 2
Yukawa, Tomoya
Fujimori, Ikuo
Kamei, Taku
Nakada, Yoshihisa
Sakauchi, Nobuki
Yamada, Masami
Ohba, Yusuke
Ueno, Hiroyuki
Takiguchi, Maiko
Kuno, Masako
Kamo, Izumi
Nakagawa, Hideyuki
Fujioka, Yasushi
Igari, Tomoko
Ishichi, Yuji
Tsukamoto, Tetsuya
BIOORGANIC & MEDICINAL CHEMISTRY, 2016, 24 (14) : 3207 - 3217
[28] Structure-activity relationships of the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ol series of monoamine reuptake inhibitors
Mahaney, Paige E.
Kim, Callain Y.
Coghlan, Richard D.
Cohn, Stephen T.
Heffernan, Gavin D.
Huselton, Christine A.
Terefenko, Eugene A.
Vu, An T.
Zhang, Puwen
Burroughs, Kevin D.
Cosmi, Scott A.
Bray, Jenifer A.
Johnston, Grace H.
Deecher, Darlene C.
Trybulski, Eugene J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (19) : 5807 - 5810
[29] Design, Synthesis, and In Vitro Evaluation of Potential West Nile Virus Protease Inhibitors Based on the 1-Oxo-1,2,3,4-tetrahydroisoquinoline and 1-Oxo-1,2-dihydroisoquinoline Scaffolds
Dou, Dengfeng
Viwanathan, Prasanth
Li, Yi
He, Guijia
Alliston, Kevin R.
Lushington, Gerald H.
Brown-Clay, Joshua D.
Padmanabhan, R.
Groutas, William C.
JOURNAL OF COMBINATORIAL CHEMISTRY, 2010, 12 (06): : 836 - 843
[30] Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists
Dounay, Amy B.
Barta, Nancy S.
Campbell, Brian M.
Coleman, Corey
Collantes, Elizabeth M.
Denny, Lynne
Dutta, Satavisha
Gray, David L.
Hou, Dongfeng
Iyer, Rathna
Maiti, Samarendra N.
Ortwine, Daniel F.
Probert, Al
Stratman, Nancy C.
Subedi, Rajendra
Whisman, Tammy
Xu, Wenjian
Zoski, Kim
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (03) : 1114 - 1117

← 1 2 3 4 5 →