DESIGN AND SYNTHESIS OF NOVEL AND POTENT MONOAMINE-OXIDASE INHIBITORS

Reversible and selective monoamine oxidase-A inhibitors (RIMA's) like moclobemide (Aurorix(R)) have rehabilitated the use of MAO inhibitors as drugs of choice in depression. Starting from the structure of moclo bemide, we tried to identify novel types of MAO inhibitors by bioisost eric replacement of the amide group. 2-Aminomethyl-5-phenylpyrroles re tained some in vitro activity and served as a starting point for the c onstruction of restricted rotation analogues. 3,4-Dihydro-6-phenylpyrr olo[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 subse quently optimized. A 'lipophilic linker' between phenyl and pyrrole ri ng proved exceedingly useful to improve affinity and led to the benzo [g]pyrazino[1,2-a]indole ring system. Synthetic procedures starting fr om substituted 1-tetralones allowed the synthesis of substituted deriv atives of this ring system. Once the optimal substitution pattern had been identified, facile synthesis of derivatives was achieved from aro matic triflates by Stifle 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 w as in the nanomolar or even sub-nanomolar range (for monoamine oxidase -A). In conclusion, benzo[g]pyrazino[1,2-a]indoles have been identifie d as a new class of reversible and highly potent monoamine oxidase inh ibitors.