New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds

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New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds. / Heng, Sabrina; Tieu, William; Hautmann, Stephanie; Kuan, Kevin; Pedersen, Daniel Sejer; Pietsch, Markus; Gütschow, Michael; Abell, Andrew D.

In: Bioorganic & Medicinal Chemistry, Vol. 19, No. 24, 15.12.2011, p. 7453-7463.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Heng, S, Tieu, W, Hautmann, S, Kuan, K, Pedersen, DS, Pietsch, M, Gütschow, M & Abell, AD 2011, 'New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds', Bioorganic & Medicinal Chemistry, vol. 19, no. 24, pp. 7453-7463. https://doi.org/10.1016/j.bmc.2011.10.042

APA

Heng, S., Tieu, W., Hautmann, S., Kuan, K., Pedersen, D. S., Pietsch, M., ... Abell, A. D. (2011). New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds. Bioorganic & Medicinal Chemistry, 19(24), 7453-7463. https://doi.org/10.1016/j.bmc.2011.10.042

Vancouver

Heng S, Tieu W, Hautmann S, Kuan K, Pedersen DS, Pietsch M et al. New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds. Bioorganic & Medicinal Chemistry. 2011 Dec 15;19(24):7453-7463. https://doi.org/10.1016/j.bmc.2011.10.042

Author

Heng, Sabrina ; Tieu, William ; Hautmann, Stephanie ; Kuan, Kevin ; Pedersen, Daniel Sejer ; Pietsch, Markus ; Gütschow, Michael ; Abell, Andrew D. / New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds. In: Bioorganic & Medicinal Chemistry. 2011 ; Vol. 19, No. 24. pp. 7453-7463.

Bibtex

@article{4930e4c9f43c41f4a85ef921322c9b85,
title = "New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds",
abstract = "We present a new class of inhibitors of pancreatic cholesterol esterase (CEase) based on 'priviledged' 5-benzylidenerhodanine and 5-benzylidene-2,4-thiazolidinedione structural scaffolds. The lead structures (5-benzylidenerhodanine 4a and 5-benzylidene-2,4-thiazolidinedione 4b) were identified in an in-house screening and these inhibited CEase with some selectivity over another serine hydrolase, acetylcholinesterase (AChE) (4a, CEase IC(50)=1.76µM vs AChE IC(50)=5.14µM and 4b, CEase IC(50)=5.89µM vs AChE IC(50) >100µM). A small library of analogs (5a-10a) containing a core amino acid in place of the glycerol group of the lead structures, was prepared to explore other potential binding interaction with CEase. These analogs inhibited CEase with IC(50) values ranging from 1.44 to 85µM, with the majority exhibiting some selectivity for CEase versus AChE. The most potent compound of the library (10a) had 17-fold selectivity over AChE. We also report molecular docking (with CEase) and detailed kinetic analysis on the amino acid analogs to further understand the associated structure-activity relationships.",
keywords = "The Faculty of Pharmaceutical Sciences",
author = "Sabrina Heng and William Tieu and Stephanie Hautmann and Kevin Kuan and Pedersen, {Daniel Sejer} and Markus Pietsch and Michael G{\"u}tschow and Abell, {Andrew D}",
note = "Keywords: cholesterol esterase; acetylcholinesterase; privileged scaffolds; rhodanine; thiazolidinedione",
year = "2011",
month = "12",
day = "15",
doi = "10.1016/j.bmc.2011.10.042",
language = "English",
volume = "19",
pages = "7453--7463",
journal = "Bioorganic & Medicinal Chemistry",
issn = "0968-0896",
publisher = "Pergamon Press",
number = "24",

}

RIS

TY - JOUR

T1 - New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds

AU - Heng, Sabrina

AU - Tieu, William

AU - Hautmann, Stephanie

AU - Kuan, Kevin

AU - Pedersen, Daniel Sejer

AU - Pietsch, Markus

AU - Gütschow, Michael

AU - Abell, Andrew D

N1 - Keywords: cholesterol esterase; acetylcholinesterase; privileged scaffolds; rhodanine; thiazolidinedione

PY - 2011/12/15

Y1 - 2011/12/15

N2 - We present a new class of inhibitors of pancreatic cholesterol esterase (CEase) based on 'priviledged' 5-benzylidenerhodanine and 5-benzylidene-2,4-thiazolidinedione structural scaffolds. The lead structures (5-benzylidenerhodanine 4a and 5-benzylidene-2,4-thiazolidinedione 4b) were identified in an in-house screening and these inhibited CEase with some selectivity over another serine hydrolase, acetylcholinesterase (AChE) (4a, CEase IC(50)=1.76µM vs AChE IC(50)=5.14µM and 4b, CEase IC(50)=5.89µM vs AChE IC(50) >100µM). A small library of analogs (5a-10a) containing a core amino acid in place of the glycerol group of the lead structures, was prepared to explore other potential binding interaction with CEase. These analogs inhibited CEase with IC(50) values ranging from 1.44 to 85µM, with the majority exhibiting some selectivity for CEase versus AChE. The most potent compound of the library (10a) had 17-fold selectivity over AChE. We also report molecular docking (with CEase) and detailed kinetic analysis on the amino acid analogs to further understand the associated structure-activity relationships.

AB - We present a new class of inhibitors of pancreatic cholesterol esterase (CEase) based on 'priviledged' 5-benzylidenerhodanine and 5-benzylidene-2,4-thiazolidinedione structural scaffolds. The lead structures (5-benzylidenerhodanine 4a and 5-benzylidene-2,4-thiazolidinedione 4b) were identified in an in-house screening and these inhibited CEase with some selectivity over another serine hydrolase, acetylcholinesterase (AChE) (4a, CEase IC(50)=1.76µM vs AChE IC(50)=5.14µM and 4b, CEase IC(50)=5.89µM vs AChE IC(50) >100µM). A small library of analogs (5a-10a) containing a core amino acid in place of the glycerol group of the lead structures, was prepared to explore other potential binding interaction with CEase. These analogs inhibited CEase with IC(50) values ranging from 1.44 to 85µM, with the majority exhibiting some selectivity for CEase versus AChE. The most potent compound of the library (10a) had 17-fold selectivity over AChE. We also report molecular docking (with CEase) and detailed kinetic analysis on the amino acid analogs to further understand the associated structure-activity relationships.

KW - The Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.bmc.2011.10.042

DO - 10.1016/j.bmc.2011.10.042

M3 - Journal article

VL - 19

SP - 7453

EP - 7463

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 24

ER -

ID: 35458556