Reactions of functionalized sulfonamides: application to lowering the lipophilicity of cytosolic phospholipase A2alpha inhibitors.
The cPLA(2)alpha inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays but have high plogD(7.4). To address these issues, reactions of electrophilic sulfonamides 9-12 were employed to incorporate various heterocyclic or heteroatom-based reagents into cPLA(2)alpha inhibitors. For example, reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10 and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided an efficient way to introduce polarity into cPLA(2)alpha inhibitors. Finally, we report the first application of (2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD(7.4) values 3-4 units lower than previously synthesized compounds and yet maintain in vitro potency.
Chen
Lihren
L
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA.
Wang
Weiheng
W
Lee
Katherine L
KL
Shen
Marina W H
MW
Murphy
Elizabeth A
EA
Zhang
Wen
W
Xu
Xin
X
Tam
Steve
S
Nickerson-Nutter
Cheryl
C
Goodwin
Debra G
DG
Clark
James D
JD
McKew
John C
JC
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D057927:Hydrophobic and Hydrophilic Interactions; D051381:Rats; D013329:Structure-Activity Relationship; D013440:Sulfides; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013440:Sulfides; D013449:Sulfonamides; D054513:Group IV Phospholipases A2