Synthesis and evaluation of substrate-mimicking cytosolic phospholipase A2 inhibitors--reducing the lipophilicity of the arachidonyl chain isostere.
The high lipophilicity of a series of cytosolic phospholipase A(2) inhibitors has been reduced by the modification of a decyloxyphenyl chain designed to mimic the arachidonyl group of the natural substrate. These changes have resulted in an improvement in the whole cell potency of the inhibitors.
Walters
Iain
I
Departments of Medicinal Chemistry, Molecular Biology, and Discovery BioScience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom. iain.walters@astrazeneca.com
Bennion
Colin
C
Connolly
Stephen
S
Croshaw
Pamela J
PJ
Hardy
Kim
K
Hartopp
Paul
P
Jackson
Clive G
CG
King
Sarah J
SJ
Lawrence
Louise
L
Mete
Antonio
A
Murray
David
D
Robinson
David H
DH
Stein
Linda
L
Wells
Edward
E
John Withnall
W
W
D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2