Bio(iso)steric replacement is a powerful tool for the Medicinal chemist [1]. Two functional groups should be called isoster if they share similar physico-chemical properties and bioisosters if they have the same biological profile. It could be said that while chemistry rules the isosteric similarity between groups, only the biological target will be able to answer positively to the following bioisosteric hypothesis. In recent years [2] our group at DSTF is directing its efforts towards the investigation of a general tool able to mimic the carboxyl group in a universal “alkahest” way. Instead of deeply investigating a single moiety, we focused our attention on a pool of over ten acidic hydroxylated pentatomic heterocyclic systems. The result of such affords was the development of a flexible tool capable to be adapted to the requirements of different targets both in terms of acidity as well as general chemio-physical profiles. In this occasion is presented a first successfully application of this approach directed toward the development of potent human Dihydroorotate Dehydrogenase (hDHODH) inhibitors, as possible immunosuppressive agents. Starting from structural information rising from both Brequinar and A771726, the Lefluonimde metabolite, a scaffold hopping approach using our heterocyclic panel afforded models in the low nM range on hDHODH. [1] Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. J Med Chem. 2011, 54(8), 2529-91. [2] Lolli, M.L.; Giorgis, M.; Tosco P., Foti A., Fruttero, R.; Gasco, A New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy-1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold Eur. J Med Chem. 2012, 49, 102-109

Toward a bioisosteric alkahest: Targeting the human dehydroorotate dehydrogenase (hDHODH) by a scaffold hopping bioisosteric approach using hydroxylated pentaatomic heterocycles

249th National Meeting (2015)

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