Design and Synthesis of Novel and Potent Monoamine Oxidase Inhibitors

Abstract

Reversible and selective monoamine oxidase-A inhibitors (RIMA's) like moclobemide (Aurorix^®) have rehabilitated the use of MAO inhibitors as drugs of choice in depression. Starting from the structure of moclobemide, we tried to identify novel types of MAO inhibitors by bioisosteric replacement of the amide group. 2-Aminomethyl-5-phenylpyrroles retained some in vitro activity and served as a starting point for the construction of restricted rotation analogues. 3,4-Dihydro-6-phenylpyrrolo[1,2-a]pyrazines were the most interesting members of a family of 6-, 7-, and 8-phenyl-substituted pyrrolo[1,2-a]pyrazines and were subsequently optimized. A 'lipophilic linker' between phenyl and pyrrole ring proved exceedingly useful to improve affinity and led to the benzo[g]pyrazino[1,2-a]indole ring system. Synthetic procedures starting from substituted 1-tetralones allowed the synthesis of substituted derivatives of this ring system. Once the optimal substitution pattern had been identified, facile synthesis of derivatives was achieved from aromatic triflates by Stille or Suzuki coupling. In this series selective and reversible monoamine oxidase-A inhibitors as well as mixed MAO-A and B inhibitors were identified. Affinity of this compounds for MAO was in the nanomolar or even sub-nanomolar range (for monoamine oxidase-A). In conclusion, benzo[g]pyrazino[1,2-a]indoles have been identified as a new class of reversible and highly potent monoamine oxidase inhibitors.