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 sub-micromolar inhibitory activity against IMPDH2 (Ki ∼ 0.2 μM). 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 (Ki = 0.3–0.4 μM) than the corresponding parent bis(phosphonate)s 2 and 3 (Ki = 0.04–0.11μM), respectively.

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