Indazole- and Indole-5-carboxamides: Selective and Reversible Monoamine Oxidase B Inhibitors with Subnanomolar Potency

Abstract

Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.

Synthetic approaches and pharmaceutical applications of chloro-containing molecules for drug discovery: A critical review

“…Compound 325 was screened for its monoamine oxidase B inhibition activity and showed potent activity with IC 50 values of 0.227 nM against human MAO-B and 1300 nM against human MAO-A enzymes. Future efforts will be directed toward further improving the compounds' drug-like properties with regard to water-solubility, bioavailability, metabolism, and toxicity and to evaluate the new MAO-B inhibitors in relevant animal models [109].…”

Identification of Indole‐Based Chalcones: Discovery of a Potent, Selective, and Reversible Class of MAO‐B Inhibitors

“…The information regarding the exploration of various groups at the para position of ring B system of indole‐based chalcone and its effect of MAO inhibition is not explored so far. 3‐Acetyl indole moiety was selected as starting reagent for the synthesis of various indole‐based chalcones, since indole is often present in compounds with remarkable MAO inhibitory activities . Accordingly to these results, in this work we describe the synthesis, biological evaluation, and molecular modeling of indole‐based chalcone derivatives as selective MAO‐B inhibitors.…”

Synthesis of a series of unsaturated ketone derivatives as selective and reversible monoamine oxidase inhibitors

“…7 MAO-A is mainly located in catecholaminergic neurons and selectively inhibited by low concentrations of clorgyline (1), whereas MAO-B is primarily found in serotonergic neurons and astrocytes, and selectively inhibited by L-deprenyl (selegiline) (Figure 1). 8 The activity and the expression levels of MAO-B in the human brain, but not those of MAO-A, increase with age and particularly its activity is significantly increased in the substantia nigra (SN) of patients with Parkinson's diseases (PD). Therefore, selective MAO-B inhibitors (selegiline (2) and rasagiline (3)) are used solely, or in combination with the dopamine prodrug levodopa to reduce the metabolic degradation of dopamine for the symptomatic treatment of PD.…”