Synthesis and Monoamine Oxidase Inhibitory Activity of 3‐Substituted 5<i>H</i>‐Indeno[1,2‐<i>c</i>]pyridazines

Kneubühler, Silvia; Testa, Bernard; Carta, V.; Altomare, Cosimo; Carotti, Angelo

doi:10.1002/hlca.19930760514

Cited by 31 publications

(10 citation statements)

References 19 publications

(8 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a part of our ongoing research in this field, [40][41][42][43][44][45][46][47] herein we report the design, synthesis, and biochemical evaluation of a new series of coumarins that maintained the potent and selective MAO-B inhibition found for this class of compounds [48][49][50] but that exhibited more appropriate physicochemical and pharmacokinetic properties for clinical applications as novel therapeutics of neurological disorders. In fact, most of the potent and selective MAO-B coumarin inhibitors studied so far have generally displayed too high lipophilicity and poor aqueous solubility, and this might strongly limit their investigations even at the level of experimental preclinical profiling.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Class of Potent Coumarin Monoamine Oxidase B Inhibitors: Development and Biopharmacological Profiling of 7-[(3-Chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one Methanesulfonate (NW-1772) as a Highly Potent, Selective, Reversible, and Orally Active Monoamine Oxidase B Inhibitor

et al. 2009

Self Cite

View full text Add to dashboard Cite

In an effort to discover novel selective monoamine oxidase (MAO) B inhibitors with favorable physicochemical and pharmacokinetic profiles, 7-[(m-halogeno)benzyloxy]coumarins bearing properly selected polar substituents at position 4 were designed, synthesized, and evaluated as MAO inhibitors. Several compounds with MAO-B inhibitory activity in the nanomolar range and excellent MAO-B selectivity (selectivity index SI > 400) were identified. Structure-affinity relationships and docking simulations provided valuable insights into the enzyme-inhibitor binding interactions at position 4, which has been poorly explored. Furthermore, computational and experimental studies led to the identification and biopharmacological characterization of 7-[(3-chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one methanesulfonate 22b (NW-1772) as an in vitro and in vivo potent and selective MAO-B inhibitor, with rapid blood-brain barrier penetration, short-acting and reversible inhibitory activity, slight inhibition of selected cytochrome P450s, and low in vitro toxicity. On the basis of this preliminary preclinical profile, inhibitor 22b might be viewed as a promising clinical candidate for the treatment of neurodegenerative diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Class of Potent Coumarin Monoamine Oxidase B Inhibitors: Development and Biopharmacological Profiling of 7-[(3-Chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one Methanesulfonate (NW-1772) as a Highly Potent, Selective, Reversible, and Orally Active Monoamine Oxidase B Inhibitor

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…Activity in Rat-Brain-Mitochondria. Compounds 1 ± 22 were tested for their inhibitory activities on MAO-A and -B in rat-brain mitochondrial suspensions [26]. Incubations were carried out at pH 7.40 (Na 2 HPO 4 /KH 2 PO 4 , made isotonic with KCl) at 378.…”

mentioning

confidence: 99%

Lipophilicity Plays a Major Role in Modulating the Inhibition of Monoamine Oxidase B by 7‐Substituted Coumarins

Carotti

Altomare

Catto

et al. 2006

Chemistry & Biodiversity

Self Cite

View full text Add to dashboard Cite

A series of coumarin derivatives (1-22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC(50) values in the micromolar to low-nanomolar range. A structure-activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r(2)=0.72) between pIC(50) and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1 h after intraperitoneal administration of high doses (100 and 300 mumol kg(-1)), revealing its ability to cross the blood-brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues.

show abstract

“…The spectral properties of the adduct (UV characteristics included a shoulder between 326 and 332 nm) were consistent with the flavin moiety bearing a phenyl group at position 4a (110). Furthermore, evidence in support of adduct 110 has been generated from mass spectrometry and infrared analysis of model chemical reactions between synthetic flavins and 106.126 This strongly suggested that the reaction pathway involved initial dehydrogenation of 106 to form the reactive intermediate 107 as predicted by Hellerman.…”

Section: A Hydrazinesmentioning

confidence: 67%