6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists

Orain, David; Ofner, Silvio; Koller, Manuel; Carcache, David A.; Froestl, Wolfgang; Allgeier, Hans; Rasetti, Vittorio; Nozulak, Joachim; Mattes, Henri; Soldermann, Nicolas; Desrayaud, Sandrine; Kallen, Joerg; Lingenhoehl, Kurt; Urwyler, Stephan

doi:10.1016/j.bmcl.2011.12.009

Cited by 19 publications

(12 citation statements)

References 13 publications

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“…Additional quinoxalinediones with in vivo anticonvulsant activity were described, such as YM872 , YM90K , ZK 200775 (MPQX, fanapanel) , and AMP397 (becampanel) . Some structurally dissimilar competitive AMPA receptor antagonists with in vivo anticonvulsant activity were also identified, including the pyrazine derivative RPR117824 ; isatin oximes, such as NS1209 (SPD 502) , which also inhibits GluK1 kainate receptors; a series of quinazoline‐2,4‐dione sulfonamides ; and the quinazolin‐2‐one Ro 48‐8587 . NS1209 is not orally active and was investigated as an intravenous agent for the treatment of status epilepticus .…”

Section: Antagonist Pharmacology Of Ampa Receptorsmentioning

confidence: 99%

AMPA receptors as a molecular target in epilepsy therapy

2013

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Epileptic seizures occur as a result of episodic abnormal synchronous discharges in cerebral neuronal networks. Although a variety of nonconventional mechanisms may play a role in epileptic synchronization, cascading excitation within networks of synaptically connected excitatory glutamatergic neurons is a classical mechanism. As is the case throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting glutamate-mediated excitation, AMPA receptor antagonists markedly reduce or abolish epileptiform activity in in vitro preparations and confer seizure protection in a broad range of animal seizure models. NMDA receptors may also contribute to epileptiform activity, but NMDA receptor blockade is not sufficient to eliminate epileptiform discharges. AMPA receptors move into and out of the synapse in a dynamic fashion in forms of synaptic plasticity, underlying learning and memory. Often the trigger for these dynamic movements is activation of NMDA receptors. While NMDA receptor antagonists inhibit these forms of synaptic plasticity, AMPA receptor antagonists do not impair synaptic plasticity and do not inhibit memory formation or retrieval. The demonstrated clinical efficacy of perampanel, a high-potency, orally active noncompetitive AMPA receptor antagonist, supports the concept that AMPA receptors are critical to epileptic synchronization and the generation and spread of epileptic discharges in human epilepsy.

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Section: Antagonist Pharmacology Of Ampa Receptorsmentioning

confidence: 99%

AMPA receptors as a molecular target in epilepsy therapy

2013

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“…X‐ray analysis of hGluA2 complexes with a number of close analogues of 1 E allowed us to identify important ligand–receptor interactions. The 3D structure highlights the exquisite complementarity of the quinazolinedione scaffold for the AMPA binding site.…”

Section: Figurementioning

confidence: 99%

“…[32] In line with published data, the new analogues embedding these 6-substituents showedh igh affinity for the AMPAr eceptor.H owever,d espite good improvement in binding affinity,t he resulting products showed no in vivoa ctivity, following oral administration of the drug, as shown in Table 1. Pharmacokinetic profiling of 1E [25] indicated av ery low bioavailability of this compound (10 %), which may explain its lack of oral activity.…”

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confidence: 99%

“…The next challenge was thus to prepare quinazolinedione derivatives which would show oral activity in animal models of epilepsy.T he availability of an umber of in-house X-ray crystal structures in conjunction with molecular modelling efforts were importanta ssets to assist the selection of new substituents which would potentially interactw ith the receptor, keeping in mind that the ultimate goal was to influencet he pharmacokinetic properties of the molecules in order to gain in vivo activity. X-ray analysiso fh GluA2 complexes with an umber of close analogues of 1E [24,25,40] allowed us to identify important ligand-receptor interactions. The 3D structure highlights the exquisite complementarity of the quinazolinediones caffold for the AMPAbinding site.…”

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Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist

et al. 2016

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A series of potent quinazolinedione sulfonamide antagonists of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor were designed and synthesized. The structure–activity relationships (SAR) and in vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N‐[7‐isopropyl‐6‐(2‐methylpyrazol‐3‐yl)‐2,4‐dioxo‐1H‐quinazolin‐3‐yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)‐induced generalized tonic–clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy. The X‐ray crystal structure of selurampanel bound to the AMPA receptor hGluA was also obtained.

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“…21,22) Further investigations on methaquolone led to the development of the 8-hydrazinocarboxylate derivative IV which exhibited high anticonvulsant profile in pentylenetetrazole (PTZ) and maximal electroshock model (MES) assays. 23) Recently, the 2-methylsulfonamido-quinazolinedione derivative V was identified with a low ED 50 in animal model of anticonvulsant activity after oral dosage 24) (Fig. 2).…”

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Design and Synthesis of Some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl]quinazolin-4(3<i>H</i>)-one Derivatives as Potential Anticonvulsant Agents

Abbas

Awadallah

Ibrahim

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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Series of 2,3-disubstituted quinazolinone derivatives and a [1,2,4]triazino[2,3-c]quinazolinone featuring the pharmacophoric elements of anticonvulsant drugs were designed and synthesized. Target compounds were screened for their anticonvulsant activity using the subcutaneous pentylenetetrazole (s.c. PTZ) and maximal electroshock (MES) models. The s.c. PTZ test showed that the most active compound was the amide derivative 9c having a protective dose 50 (PD 50 ) of 200.53 µmol/kg (PD 50 of phenobarbitone=62.18 µmol/kg); nevertheless, this low potency is outweighed by the much higher safety profile of 9c (LD 50 >3000 mg/kg). In the MES screening, seven compounds were equal to or more active than phenytoin; some of these compounds were less neurotoxic than phenytoin. Few compounds such as 9c and 10 were effective in both models. LD 50 for the most active compounds was calculated.Key words quinazolinone; pentylenetetrazole model; maximal electroshock model; anticonvulsant activity; LD 50 ; neurotoxicity Epilepsy is an all-pervading neurological disorder characterized by recurrent seizures and affecting about 1% of the world's population. In the last few decades, many efforts devoted for the development of novel therapeutics resulted in the availability of several newer agents as promising anticonvulsants.1,2) The efficacy of many of the marketed antiepileptic drugs is greatly compromised by severe side effects such as ataxia, drowsiness, gingival hyperplasia, gastrointestinal disturbances, and megaloblastic anaemia. Moreover, about 30% of patients have uncontrolled seizures.3-8) Therefore, continued search for safer and more effective anticonvulsants is urgently necessary.The insufficient information on the cellular mechanism of epilepsy in human and the complex mechanism of action of most of the antiepileptic drugs makes it difficult to use rational methodologies in the discovery of new antiepileptic drugs. Therefore, another design approach based on the existence of different pharmacophores that were established through the analysis of structural characteristics of clinically effective drugs as well as other antiepileptic compounds was adopted.9-11) In the literatures, it is well documented that one of the important core fragments is defined by the presence of: i) hydrogen donor/acceptor unit (HAD), ii) one electron donor atom (D), and iii) a hydrophobic domain (A) (aryl ring substituted/unsubstituted).12-15) These structural features were found in the first generation drugs including the well-established antiepileptics such as carbamazepine or phenytoin, and the newest drugs e.g., Felbamate; and in the second generation antiepileptic drugs and the drugs in clinical trial (Fig. 1). Efforts devoted in the recent years based on this pharmacophore model resulted in the availability of several newer drugs (such as retigabine, tiagabine, lamotrigine, pregabalin, stiripentol, zonisamide, topiramate, levetiracetam) as promising antiepileptics. 1)Literature survey revealed that quinazoline is a privileged lead molecule fo...

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6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists

Cited by 19 publications

References 13 publications

AMPA receptors as a molecular target in epilepsy therapy

AMPA receptors as a molecular target in epilepsy therapy

Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist

Design and Synthesis of Some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl]quinazolin-4(3<i>H</i>)-one Derivatives as Potential Anticonvulsant Agents

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