Design and synthesis of potent carboxylic acid DGAT1 inhibitors with high cell permeability.
A series of potent carboxylic acid DGAT1 inhibitors with high permeability were developed from a virtual screening hit. Strategies were employed to reduce Pgp substrate recognition and increase passive permeability, resulting in the discovery of a series showing good inhibition of cellular triglyceride synthesis. The mutagenic potential of prospective metabolites was evaluated in the Ames assay, and one aniline was shown to be devoid of mutagenicity.
Prosidion Ltd, Windrush Court, Watlington Road, Oxford, OX4 6LT, United Kingdom.
Ustav
U
Bali
Oscar
O
Barba
Graham
G
Dawson
William T
WT
Gattrell
James G
JG
Horswill
David A
DA
Pan
Martin J
MJ
Procter
Chrystelle M
CM
Rasamison
Colin P
CP
Sambrook Smith
Amanda
A
Taylor-Warne
Philippe
P
Wong-Kai-In
D018938:Caco-2 Cells; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010539:Permeability / Q000187:drug effects; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase