Universität zu Köln

Heng, Sabrina, Tieu, William ORCID: 0000-0002-7161-4152, Hautmann, Stephanie, Kuan, Kevin, Pedersen, Daniel Sejer ORCID: 0000-0003-3926-7047, Pietsch, Markus, Guetschow, Michael and Abell, Andrew D. (2011). New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds. Bioorg. Med. Chem., 19 (24). S. 7453 - 7464. OXFORD: PERGAMON-ELSEVIER SCIENCE LTD. ISSN 1464-3391

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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 IC50 = 1.76 mu M vs AChE IC50 = 5.14 mu M and 4b, CEase IC50 = 5.89 mu M vs AChE IC50 > 100 mu M). 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 IC50 values ranging from 1.44 to 85 mu M, 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. (C) 2011 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Heng, Sabrina UNSPECIFIED UNSPECIFIED UNSPECIFIED Tieu, William UNSPECIFIED orcid.org/0000-0002-7161-4152 UNSPECIFIED Hautmann, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuan, Kevin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pedersen, Daniel Sejer UNSPECIFIED orcid.org/0000-0003-3926-7047 UNSPECIFIED Pietsch, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Guetschow, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Abell, Andrew D. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-483340
DOI:	10.1016/j.bmc.2011.10.042
Journal or Publication Title:	Bioorg. Med. Chem.
Volume:	19
Number:	24
Page Range:	S. 7453 - 7464
Date:	2011
Publisher:	PERGAMON-ELSEVIER SCIENCE LTD
Place of Publication:	OXFORD
ISSN:	1464-3391
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ALPHA/BETA-HYDROLASE FOLD; PYRROLIDINE INHIBITORS; CRYSTAL-STRUCTURE; ACETYLCHOLINESTERASE; LIPASE; ABSORPTION; POTENT; SITE; DERIVATIVES; METABOLISM Multiple languages Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48334