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 journal › Journal article › Research › peer-review
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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 - Former Faculty of Pharmaceutical Sciences
U2 - 10.1016/j.bmc.2011.10.042
DO - 10.1016/j.bmc.2011.10.042
M3 - Journal article
C2 - 22075233
VL - 19
SP - 7453
EP - 7463
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 24
ER -
ID: 35458556