PMID- 28726524 OWN - NLM STAT- MEDLINE DCOM- 20171009 LR - 20200225 IS - 1475-6374 (Electronic) IS - 1475-6366 (Print) IS - 1475-6366 (Linking) VI - 32 IP - 1 DP - 2017 Dec TI - Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration. PG - 960-967 LID - 10.1080/14756366.2017.1344980 [doi] AB - 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 (pIC(50 )>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 Fe(2+) and Fe(3+) ions using UV-visible spectroscopy. FAU - Tzvetkov, Nikolay T AU - Tzvetkov NT AD - a NTZ Lab Ltd. , Sofia , Bulgaria. FAU - Antonov, Liudmil AU - Antonov L AD - b Bulgarian Academy of Sciences , Institute of Organic Chemistry, Centre of Phytochemistry , Sofia , Bulgaria. LA - eng PT - Journal Article PL - England TA - J Enzyme Inhib Med Chem JT - Journal of enzyme inhibition and medicinal chemistry JID - 101150203 RN - 0 (Indazoles) RN - 0 (Monoamine Oxidase Inhibitors) RN - E1UOL152H7 (Iron) RN - EC 1.4.3.4 (Monoamine Oxidase) SB - IM MH - Binding Sites/drug effects MH - Brain/*metabolism MH - Humans MH - Indazoles/chemical synthesis/chemistry/*pharmacology MH - Iron/*metabolism MH - Models, Molecular MH - Molecular Structure MH - Monoamine Oxidase/*metabolism MH - Monoamine Oxidase Inhibitors/chemical synthesis/chemistry/*pharmacology MH - Solubility MH - Structure-Activity Relationship PMC - PMC6445166 OTO - NOTNLM OT - Alzheimer's disease OT - MAO inhibitors OT - Parkinson's disease OT - free energy calculations OT - iron chelators EDAT- 2017/07/21 06:00 MHDA- 2017/10/11 06:00 PMCR- 2017/07/20 CRDT- 2017/07/21 06:00 PHST- 2017/07/21 06:00 [entrez] PHST- 2017/07/21 06:00 [pubmed] PHST- 2017/10/11 06:00 [medline] PHST- 2017/07/20 00:00 [pmc-release] AID - 1344980 [pii] AID - 10.1080/14756366.2017.1344980 [doi] PST - ppublish SO - J Enzyme Inhib Med Chem. 2017 Dec;32(1):960-967. doi: 10.1080/14756366.2017.1344980.