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

[41] Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2-Methoxy 1, 8 Naphthyridine 3-Carboxamides as 5-HT3 Receptor Antagonists
Mahesh, Radhakrishnan
Dhar, Arghya Kusum
Jindal, Ankur
Bhatt, Shvetank
CHEMICAL BIOLOGY & DRUG DESIGN, 2014, 83 (05) : 583 - 591
[42] Radical polymerization of acrylonitrile initiated by triphenyl stibonium 1,2,3,4 tetraphenylcyclo-pentadiene ylide
Srivastava, A. K.
Chaurasia, A. K.
Sharma, S.
Mishra, G.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES INDIA SECTION A-PHYSICAL SCIENCES, 2007, 77A : 93 - 97
[43] Evaluation of antidepressant activity of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol, a β-substituted phenylethylamine in mice
Dhir, Ashish
Malik, Sneh
Kessar, S. V.
Singh, K. N.
Kulkarni, S. K.
EUROPEAN NEUROPSYCHOPHARMACOLOGY, 2011, 21 (09) : 705 - 714
[44] Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors
Sechi, Mario
Rizzi, Giuseppe
Bacchi, Alessia
Carcelli, Mauro
Rogolino, Dominga
Pala, Nicolino
Sanchez, Tino W.
Taheri, Laleh
Dayam, Raveendra
Neamati, Nouri
BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (07) : 2925 - 2935
[45] SYNTHESIS AND ENANTIOSELECTIVITY OF OPTICALLY-ACTIVE 1-SUBSTITUTED AND 3-SUBSTITUTED 4-PHENYL-1,2,3,4-TETRAHYDROISOQUINOLIN-4-OLS AND RELATED-COMPOUNDS AS NOREPINEPHRINE POTENTIATORS
KIHARA, M
IKEUCHI, M
ADACHI, S
NAGAO, Y
MORITOKI, H
YAMAGUCHI, M
TAIRA, Z
CHEMICAL & PHARMACEUTICAL BULLETIN, 1995, 43 (09) : 1543 - 1546
[46] Unprecedented FeCl3•6H2O-Promoted Skeleton Rearrangement of 1-Aryl-2,3,4,5-tetrahydro-1H-3-benzazepines: A New Strategy for the Synthesis of C1 Quaternary Tetrahydroisoquinolines
Zhang, Jing
Zhang, Ao
CHEMISTRY-A EUROPEAN JOURNAL, 2009, 15 (42) : 11119 - 11122
[47] NEW NOREPINEPHRINE POTENTIATORS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF 4-PHENYL-1,2,3,4-TETRAHYDROISOQUINOLIN-4-OLS
KIHARA, M
KASHIMOTO, M
KOBAYASHI, Y
NAGAO, Y
MORITOKI, H
CHEMICAL & PHARMACEUTICAL BULLETIN, 1994, 42 (01) : 67 - 73
[48] Design, synthesis and biological activity of 4-(4-benzyloxy)phenoxypiperidines as selective and reversible LSD1 inhibitors
Xi, Jiayue
Xu, Siyuan
Zhang, Lulu
Bi, Xueyuan
Ren, Yanshen
Liu, Yu-Chih
Gu, Yueqing
Xu, Yungen
Lan, Fei
Zha, Xiaoming
BIOORGANIC CHEMISTRY, 2018, 78 : 7 - 16
[49] SYNTHESIS OF 7-H-3-(1S,4S)-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-N-METHYL-L-NAPHTHALENAMINE HYDROCHLORIDE (7-H-3-SERTRALINE)
WELCH, WM
WILLIAMS, MT
JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 1993, 33 (02) : 119 - 125
[50] Design and synthesis of 5-chloro-2-hydroxy-3-triazolylbenzoic acids as HIV integrase inhibitors
Chen, Jie
Liu, Cheng-Fu
Yang, Cheng-Wen
Zeng, Cheng-Chu
Liu, Wei
Hu, Li-Ming
MEDICINAL CHEMISTRY RESEARCH, 2015, 24 (07) : 2950 - 2959

← 1 2 3 4 5 →