Heng_2011_Bioorg.Med.Chem_19_7453

Reference

Title : New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds - Heng_2011_Bioorg.Med.Chem_19_7453
Author(s) : Heng S , Tieu W , Hautmann S , Kuan K , Pedersen DS , Pietsch M , Gutschow M , Abell AD
Ref : Bioorganic & Medicinal Chemistry , 19 :7453 , 2011
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)=1.76 muM vs AChE IC(50)=5.14 muM and 4b, CEase IC(50)=5.89 muM vs AChE IC(50) >100 muM). 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 85 muM, 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.

PubMedSearch : Heng_2011_Bioorg.Med.Chem_19_7453
PubMedID: 22075233

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Citations formats

Heng S, Tieu W, Hautmann S, Kuan K, Pedersen DS, Pietsch M, Gutschow M, Abell AD (2011)
New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds
Bioorganic & Medicinal Chemistry 19 :7453

Heng S, Tieu W, Hautmann S, Kuan K, Pedersen DS, Pietsch M, Gutschow M, Abell AD (2011)
Bioorganic & Medicinal Chemistry 19 :7453