Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration

Abstract

Pharmacological and physicochemical studies of N-unsubstituted indazole-5-carboxamides (subclass I) and their structurally optimised N1-methylated analogues (subclass II), initially developed as drug and radioligand candidates for the treatment and diagnosis of Parkinson’s disease (PD), are presented. The compounds are highly brain permeable, selective, reversible, and competitive monoamine oxidase B (MAO-B) inhibitors with improved water-solubility and subnanomolar potency (pIC₅₀ >8.8). Using a well-validated, combined X-ray/modelling technology platform, we performed a semi-quantitative analysis of the binding modes of all compounds and investigated the role of the indazole N1 position for their MAO-B inhibitory activity. Moreover, compounds NTZ-1006, 1032, and 1441 were investigated for their ability to bind Fe²⁺ and Fe³⁺ ions using UV-visible spectroscopy.

Keywords:

• Alzheimer’s disease
• free energy calculations
• iron chelators
• MAO inhibitors
• Parkinson’s disease

Acknowledgements

We express our deep gratitude to Dr. Sonja Hinz and Marion Schneider. We cordially thank Dr. Matthew Segall and Nicholas Foster from Optibrium Ltd. for the generous supply of a license to run the StarDrop ADME models within SeeSAR.

Disclosure statement

The authors declare the following interests: N.T.T. is founder of NTZ Lab, a startup research and development company that synthesises and explores markets for the presented compounds.