Series of (([1,1′-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Series of (([1,1′-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity. / Ku, Therese C.; Cao, Jianjing; Won, Sung Joon; Guo, Jiqing; Camacho-Hernandez, Gisela A.; Okorom, Amarachi V.; Salomon, Kristine Walloe; Lee, Kuo Hao; Loland, Claus J.; Duff, Henry J.; Shi, Lei; Newman, Amy Hauck.

In: ACS Pharmacology and Translational Science, Vol. 7, No. 2, 2024, p. 515-532.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Ku, TC, Cao, J, Won, SJ, Guo, J, Camacho-Hernandez, GA, Okorom, AV, Salomon, KW, Lee, KH, Loland, CJ, Duff, HJ, Shi, L & Newman, AH 2024, 'Series of (([1,1′-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity', ACS Pharmacology and Translational Science, vol. 7, no. 2, pp. 515-532. https://doi.org/10.1021/acsptsci.3c00322

APA

Ku, T. C., Cao, J., Won, S. J., Guo, J., Camacho-Hernandez, G. A., Okorom, A. V., Salomon, K. W., Lee, K. H., Loland, C. J., Duff, H. J., Shi, L., & Newman, A. H. (2024). Series of (([1,1′-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity. ACS Pharmacology and Translational Science, 7(2), 515-532. https://doi.org/10.1021/acsptsci.3c00322

Vancouver

Ku TC, Cao J, Won SJ, Guo J, Camacho-Hernandez GA, Okorom AV et al. Series of (([1,1′-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity. ACS Pharmacology and Translational Science. 2024;7(2):515-532. https://doi.org/10.1021/acsptsci.3c00322

Author

Ku, Therese C. ; Cao, Jianjing ; Won, Sung Joon ; Guo, Jiqing ; Camacho-Hernandez, Gisela A. ; Okorom, Amarachi V. ; Salomon, Kristine Walloe ; Lee, Kuo Hao ; Loland, Claus J. ; Duff, Henry J. ; Shi, Lei ; Newman, Amy Hauck. / Series of (([1,1′-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity. In: ACS Pharmacology and Translational Science. 2024 ; Vol. 7, No. 2. pp. 515-532.

Bibtex

@article{33b004c310824c69a60ebd817545ec4b,
title = "Series of (([1,1′-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity",
abstract = "Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered “atypical” dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091, 1) have shown promising in vivo profiles in rodents; however, reducing hERG (human ether-{\`a}-go-go-related gene) activity, a predictor of cardiotoxicity, has remained a challenge. Herein, a series of 30 (([1,1′-biphenyl]-2-yl)methyl)sulfinylalkyl alicyclic amines was synthesized and evaluated for DAT and serotonin transporter (SERT) binding affinities. A subset of analogues was tested for hERG activity, and the IC50 values were compared to those predicted by our hERG QSAR models, which showed robust predictive power. Multiparameter optimization scores (MPO > 3) indicated central nervous system (CNS) penetrability. Finally, comparison of affinities in human DAT and its Y156F and Y335A mutants suggested that several compounds prefer an inward facing conformation indicating an atypical DAT inhibitor profile.",
keywords = "atypical dopamine transporter inhibitors, cocaine, DAT, dopamine transporter, hERG, human ether-{\`a}-go-go-related gene, MPO, multiparameter optimization score, psychostimulants, serotonin transporter",
author = "Ku, {Therese C.} and Jianjing Cao and Won, {Sung Joon} and Jiqing Guo and Camacho-Hernandez, {Gisela A.} and Okorom, {Amarachi V.} and Salomon, {Kristine Walloe} and Lee, {Kuo Hao} and Loland, {Claus J.} and Duff, {Henry J.} and Lei Shi and Newman, {Amy Hauck}",
note = "Publisher Copyright: {\textcopyright} 2024 American Chemical Society",
year = "2024",
doi = "10.1021/acsptsci.3c00322",
language = "English",
volume = "7",
pages = "515--532",
journal = "ACS Pharmacology and Translational Science",
issn = "2575-9108",
publisher = "ACS Publications",
number = "2",

}

RIS

TY - JOUR

T1 - Series of (([1,1′-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity

AU - Ku, Therese C.

AU - Cao, Jianjing

AU - Won, Sung Joon

AU - Guo, Jiqing

AU - Camacho-Hernandez, Gisela A.

AU - Okorom, Amarachi V.

AU - Salomon, Kristine Walloe

AU - Lee, Kuo Hao

AU - Loland, Claus J.

AU - Duff, Henry J.

AU - Shi, Lei

AU - Newman, Amy Hauck

N1 - Publisher Copyright: © 2024 American Chemical Society

PY - 2024

Y1 - 2024

N2 - Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered “atypical” dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091, 1) have shown promising in vivo profiles in rodents; however, reducing hERG (human ether-à-go-go-related gene) activity, a predictor of cardiotoxicity, has remained a challenge. Herein, a series of 30 (([1,1′-biphenyl]-2-yl)methyl)sulfinylalkyl alicyclic amines was synthesized and evaluated for DAT and serotonin transporter (SERT) binding affinities. A subset of analogues was tested for hERG activity, and the IC50 values were compared to those predicted by our hERG QSAR models, which showed robust predictive power. Multiparameter optimization scores (MPO > 3) indicated central nervous system (CNS) penetrability. Finally, comparison of affinities in human DAT and its Y156F and Y335A mutants suggested that several compounds prefer an inward facing conformation indicating an atypical DAT inhibitor profile.

AB - Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered “atypical” dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091, 1) have shown promising in vivo profiles in rodents; however, reducing hERG (human ether-à-go-go-related gene) activity, a predictor of cardiotoxicity, has remained a challenge. Herein, a series of 30 (([1,1′-biphenyl]-2-yl)methyl)sulfinylalkyl alicyclic amines was synthesized and evaluated for DAT and serotonin transporter (SERT) binding affinities. A subset of analogues was tested for hERG activity, and the IC50 values were compared to those predicted by our hERG QSAR models, which showed robust predictive power. Multiparameter optimization scores (MPO > 3) indicated central nervous system (CNS) penetrability. Finally, comparison of affinities in human DAT and its Y156F and Y335A mutants suggested that several compounds prefer an inward facing conformation indicating an atypical DAT inhibitor profile.

KW - atypical dopamine transporter inhibitors

KW - cocaine

KW - DAT

KW - dopamine transporter

KW - hERG

KW - human ether-à-go-go-related gene

KW - MPO

KW - multiparameter optimization score

KW - psychostimulants

KW - serotonin transporter

U2 - 10.1021/acsptsci.3c00322

DO - 10.1021/acsptsci.3c00322

M3 - Journal article

C2 - 38357284

AN - SCOPUS:85182011530

VL - 7

SP - 515

EP - 532

JO - ACS Pharmacology and Translational Science

JF - ACS Pharmacology and Translational Science

SN - 2575-9108

IS - 2

ER -

ID: 384068580