title: Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: inhibition of inosine monophosphate dehydrogenase.
abstract: Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5-8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1-3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 (K(i) approximately 0.2 microM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 (K(i)=0.3-0.4 microM) than the corresponding parent bis(phosphonate)s 2 and 3 (K(i)=0.04-0.11 microM), respectively.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.forename: Magdalena
authors.initials: M
authors.lastname: Olesiak
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Labello
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: D000227:Adenine Nucleotides / Q000737:chemistry* / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000227:Adenine Nucleotides; D013449:Sulfonamides; C110804:mycophenolic adenine dinucleotide; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; D009173:Mycophenolic Acid