Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile

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

Standard

Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile. / Okorom, Amarachi V.; Camacho-Hernandez, Gisela Andrea; Salomon, Kristine; Lee, Kuo Hao; Ku, Therese C.; Cao, Jianjing; Won, Sung Joon; Friedman, Jacob; Lam, Jenny; Paule, James; Rais, Rana; Klein, Benjamin; Xi, Zheng Xiong; Shi, Lei; Loland, Claus J.; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 67, No. 1, 2024, p. 709-727.

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

Harvard

Okorom, AV, Camacho-Hernandez, GA, Salomon, K, Lee, KH, Ku, TC, Cao, J, Won, SJ, Friedman, J, Lam, J, Paule, J, Rais, R, Klein, B, Xi, ZX, Shi, L, Loland, CJ & Newman, AH 2024, 'Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile', Journal of Medicinal Chemistry, vol. 67, no. 1, pp. 709-727. https://doi.org/10.1021/acs.jmedchem.3c02037

APA

Okorom, A. V., Camacho-Hernandez, G. A., Salomon, K., Lee, K. H., Ku, T. C., Cao, J., Won, S. J., Friedman, J., Lam, J., Paule, J., Rais, R., Klein, B., Xi, Z. X., Shi, L., Loland, C. J., & Newman, A. H. (2024). Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile. Journal of Medicinal Chemistry, 67(1), 709-727. https://doi.org/10.1021/acs.jmedchem.3c02037

Vancouver

Okorom AV, Camacho-Hernandez GA, Salomon K, Lee KH, Ku TC, Cao J et al. Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile. Journal of Medicinal Chemistry. 2024;67(1):709-727. https://doi.org/10.1021/acs.jmedchem.3c02037

Author

Okorom, Amarachi V. ; Camacho-Hernandez, Gisela Andrea ; Salomon, Kristine ; Lee, Kuo Hao ; Ku, Therese C. ; Cao, Jianjing ; Won, Sung Joon ; Friedman, Jacob ; Lam, Jenny ; Paule, James ; Rais, Rana ; Klein, Benjamin ; Xi, Zheng Xiong ; Shi, Lei ; Loland, Claus J. ; Newman, Amy Hauck. / Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile. In: Journal of Medicinal Chemistry. 2024 ; Vol. 67, No. 1. pp. 709-727.

Bibtex

@article{135c54ab162447ed95d64295682108de,

title = "Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile",

abstract = "Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.",

author = "Okorom, {Amarachi V.} and Camacho-Hernandez, {Gisela Andrea} and Kristine Salomon and Lee, {Kuo Hao} and Ku, {Therese C.} and Jianjing Cao and Won, {Sung Joon} and Jacob Friedman and Jenny Lam and James Paule and Rana Rais and Benjamin Klein and Xi, {Zheng Xiong} and Lei Shi and Loland, {Claus J.} and Newman, {Amy Hauck}",

note = "Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

year = "2024",

doi = "10.1021/acs.jmedchem.3c02037",

language = "English",

volume = "67",

pages = "709--727",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "1",

}

RIS

TY - JOUR

T1 - Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile

AU - Okorom, Amarachi V.

AU - Camacho-Hernandez, Gisela Andrea

AU - Salomon, Kristine

AU - Lee, Kuo Hao

AU - Ku, Therese C.

AU - Cao, Jianjing

AU - Won, Sung Joon

AU - Friedman, Jacob

AU - Lam, Jenny

AU - Paule, James

AU - Rais, Rana

AU - Klein, Benjamin

AU - Xi, Zheng Xiong

AU - Shi, Lei

AU - Loland, Claus J.

AU - Newman, Amy Hauck

PY - 2024

Y1 - 2024

N2 - Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.

AB - Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.

U2 - 10.1021/acs.jmedchem.3c02037

DO - 10.1021/acs.jmedchem.3c02037

M3 - Journal article

C2 - 38117239

AN - SCOPUS:85181027449

VL - 67

SP - 709

EP - 727

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -

ID: 380652271

Department of Neuroscience