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

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Chen L, Petrelli R, Olesiak M, Wilson DJ, Labello NP, Pankiewicz KW

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

Bioorg Med Chem. 2008 Aug 1;16(15):7462-9. doi: 10.1016/j.bmc.2008.06.003. Epub 2008 Jun 10.

PubMed ID

18583139 [ View in PubMed

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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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Mycophenolic acid	Inosine-5'-monophosphate dehydrogenase 1	Ki (nM)	40	N/A	N/A	Details
Mycophenolic acid	Inosine-5'-monophosphate dehydrogenase 2	Ki (nM)	10	N/A	N/A	Details