1002987-04-3Relevant articles and documents
Reactions of functionalized sulfonamides: Application to lowering the lipophilicity of cytosolic phospholipase A2α inhibitors
Chen, Lihren,Wang, Weiheng,Lee, Katherine L.,Shen, Marina W. H.,Murphy, Elizabeth A.,Zhang, Wen,Xu, Xin,Tam, Steve,Nickerson-Nutter, Cheryl,Goodwin, Debra G.,Clark, James D.,McKew, John C.
experimental part, p. 1156 - 1171 (2009/12/25)
The cPLA2α 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 cPLA2α 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 cPLA2α 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 plogD7.4 values 3- 4 units lower than previously synthesized compounds and yet maintain in vitro potency.
