New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds

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Sabrina Heng, William Tieu, Stephanie Hautmann, Kevin Kuan, Daniel Sejer Pedersen, Markus Pietsch, Michael Gütschow, Andrew D Abell

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.
OriginalsprogEngelsk
TidsskriftBioorganic & Medicinal Chemistry
Vol/bind19
Tidsskriftsnummer24
Sider (fra-til)7453-7463
ISSN0968-0896
DOI
StatusUdgivet - 15 dec. 2011

Bibliografisk note

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

ID: 35458556