We report on new, structurally optimized N-alkyl-substituted indazole-5-carboxamides, developed as potential drug and radioligand candidates for the treatment and diagnosis of Parkinson's Disease. Recently, we published remarkably potent and selective MAO-B and dually active MAO-A/B inhibitors.Those compounds had subnanomolar potency towards MAO-B and moderate activity versus MAO-A, respectively. Computer studies with a novel software tool, SeeSAR, that incorporates dehydration/desolvation and interaction terms consistently indicated paths towards their improvement. The resulting most promising drug-like derivatives that emerged are N-(3-chloro-4-fluorophenyl)-1-methyl-1H-indazole-5-carboxamide that shows pM activity vs. MAO-B and a 15.000-fold selectivity versus MAO-A, and N-(3-chloro-4-fluorophenyl)-2-methyl-2H-indazole-5-carboxamide (hMAO-B, IC50 = 8nM, hMAO-A, IC50 = 439nM). Both compounds are predicted to cross both the gastrointestinal tract and the blood-brain barrier in vitro with appropriate drug-like properties required for CNS active drugs. Further, combined single X-ray–based molecular modeling studies provided insights into the enzyme–inhibitor interactions within both MAO isoforms and a rationale for their inhibitory activity with controlled MAO-A/B selectivity – despite their small structural differences. We propose modeled binding modes and a thorough energetic analysis that are in line with safinamide and harmine's interaction patterns, allowing an outlook to further exploration of the alkyl side chain for next step lead optimization efforts.

New N-substituted indazole-5-carboxamides as subnanomolar, selective monoamine oxidase B and dually active MAO-A/B inhibitors with BBB and GI permeability

253rd National Meeting (2017)

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