Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol <i>O</i>-Methyltransferase

Ernst, Glen; Akuma, Daniel; Au, Vinh; Buchler, Ingrid P.; Byers, Spencer; Carr, Gregory V.; Defays, Sabine; León, Pablo de; Demaude, Thierry; DePasquale, Michael; Durieu, Véronique; Huang, Yaoxin; Jigorel, Émilie; Kimos, Martha; Kolobova, Anna; Montel, Florian; Moureau, Florence; Poslusney, Michael S.; Swinnen, Dominique; Vandergeten, Marie Christine; houtvin, Nathalie Van; Wei, Huijun; White, Nia A.; Wood, Martyn; Barrow, James C.

doi:10.1021/acsmedchemlett.9b00345

Cited by 9 publications

(6 citation statements)

References 18 publications

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“…The major variation in the structure of 43 and 44 was distant aryl groups at either meta-or para-position to the chelating hydroxy group of the inhibitors. 76 The in vitro experiments revealed 54 and 55 were less potent compared to 43 against h-MB-COMT, while 58 was…”

Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 97%

“…The major variation in the structure of 43 and 44 was distant aryl groups at either meta - or para -position to the chelating hydroxy group of the inhibitors. 76…”

Section: Hopos As Metalloenzyme Inhibitorsmentioning

confidence: 99%

“…70,76 Among the series, only the N-benzyl analogue 73 displayed the potency against h-MB-COMT with an IC50 value of 220 nM. Further modifications to obtain 84 and 85 resulted in an increased potency with IC 50 values of 50 and 40 nM, respectively.…”

mentioning

confidence: 99%

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Hydroxypyrone derivatives in drug discovery: from chelation therapy to rational design of metalloenzyme inhibitors

Arshad¹,

Hanif

2022

RSC Med. Chem.

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Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 97%

“…The major variation in the structure of 43 and 44 was distant aryl groups at either meta - or para -position to the chelating hydroxy group of the inhibitors. 76…”

Section: Hopos As Metalloenzyme Inhibitorsmentioning

confidence: 99%

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Hydroxypyrone derivatives in drug discovery: from chelation therapy to rational design of metalloenzyme inhibitors

Arshad¹,

Hanif

2022

RSC Med. Chem.

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“…The nitrocatechol class has been targeted in designing new compounds due to its ability to bind at the catechol binding site of the enzyme rather than the site occupied by the cofactor S‐adenosylmethionine. Examples of newly synthesized nitrocatechol COMT inhibitors include 8‐hydroxyquinoline, [20] and 3‐hydroxy‐4‐pyrimidines, [21] …”

Section: Introductionmentioning

confidence: 99%

“…However, a series of bicyclic hydroxypyridones compounds were synthesized to evaluate their potency against COMT through the addition of nitrogen to the scaffold moiety [20] . Compound 38 (c38) [2‐[(2,4‐dichlorophenyl)methyl]‐7‐hydroxy‐1,2,3,4‐tetrahydro‐8 H ‐pyrido[1,2‐ a ]pyrazin‐8‐one] was discovered to possess potent inhibitory scaffold moiety with its IC 50 estimated at 10 nM ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Insight into the Therapeutic Potential of a Bicyclic Hydroxypyridone Compound 2‐[(2,4‐Dichlorophenyl)methyl]‐7‐hydroxy‐1,2,3,4‐tetrahydro‐8H‐pyrido[1,2‐a]pyrazin‐8‐one as COMT Inhibitor in the Treatment of Parkinson's Disease: A Molecular Dynamic Simulation Approach

Soliman

Subair

Akawa

et al. 2021

Chemistry & Biodiversity

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Parkinson's disease (PD) is one of the most targeted neurodegenerative diseases in clinical research. Awareness of research is due to its increasing number of affected people worldwide. The pathology of PD has been linked to several key proteins upregulation such as the catechol O‐Methyltransferase (COMT). Hence, the synthesis of compounds possessing inhibitory capacity has been the frontline of research in recent years. Several compounds have been synthesized among which is the nitrocatechol. However, major limitations associated with the nitrocatechol scaffold include the inability to possess adequate CNS penetration properties and hepatic toxicity associated with the compounds. However, a series of bicyclic hydroxypyridones compounds were synthesized to evaluate their inhibitory potentials on COMT protein with compound 38 (c38) 2‐[(2,4‐dichlorophenyl)methyl]‐7‐hydroxy‐1,2,3,4‐tetrahydro‐8H‐pyrido[1,2‐a]pyrazin‐8‐one shown to have a 40 fold increase level coverage in its IC50 over brain exposure when compared to the other synthesized compound. The molecular dynamics method was employed to understand the nature of interaction exhibited by c38. Molecular mechanics of c38 revealed a disruptive effect on the secondary structure of COMT protein. Per residue decomposition analysis revealed similar crucial residues involved in the favorable binding of c38 and tolcapone implicated its increased inhibitory capacity on COMT in preventing PD. Free binding energy (ΔGbind) of c38 further revealed the inhibitory capacity towards COMT protein in comparison to the FDA approved tolcapone. Ligand mobility analysis of both compounds showed a timewise different mobility pattern across the simulation time frame at the active site pocket of the protein connoting the different inhibitory potency exhibited by c38 and tolcapone. Findings from this study revealed optimization of c38 could facilitate the discovery of new compounds with enhanced inhibitory properties towards COMT in treating PD.

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Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility

et al. 2020

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Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel COMT inhibitors in a set of preclinical in vivo efficacy assays to determine their viability as potential clinical candidates. We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two dopamine metabolites, in cerebrospinal fluid (CSF) and the frontal cortex. Additionally, we found the LIBD-1 significantly improved cognitive flexibility in a rat attentional set-shifting assay (ASST), an effect previously seen with the COMT inhibitor tolcapone. These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

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Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase

Cited by 9 publications

References 18 publications

Hydroxypyrone derivatives in drug discovery: from chelation therapy to rational design of metalloenzyme inhibitors

Hydroxypyrone derivatives in drug discovery: from chelation therapy to rational design of metalloenzyme inhibitors

Insight into the Therapeutic Potential of a Bicyclic Hydroxypyridone Compound 2‐[(2,4‐Dichlorophenyl)methyl]‐7‐hydroxy‐1,2,3,4‐tetrahydro‐8H‐pyrido[1,2‐a]pyrazin‐8‐one as COMT Inhibitor in the Treatment of Parkinson's Disease: A Molecular Dynamic Simulation Approach

Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility

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