Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues. inhibition of inosine monophosphate dehydrogenase.

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 submicromolar inhibitory activity against IMPDH2 (K(i) similar to 0.2 mu M). 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 mu M) than the corresponding parent bis(phosphonate)s 2 and 3 (K(i) = 0.04 -0.11 mu M), respectively