Discovery, synthesis, and structure–activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators

Kubas, Holger; Meyer, Udo; Krueger, Bjoern; Hechenberger, Mirko; Vanejevs, Maksims; Kauss, Valerjans; Ambartsumova, R. F.; Pyatkin, Ilya; Polosukhin, Alexey I.; Abel, Ulrich

doi:10.1016/j.bmcl.2013.06.049

Cited by 12 publications

(7 citation statements)

References 38 publications

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“…Then, these pharmacophore models were analyzed against their in-house evolution databases (generated from a virtual screening compound library comprising 6.5 million unique commercially available compounds) to determine the ability of each model for distinguishing between decoys and actives using ROC-AUC and early enrichment factors (EF=1% and EF=2.5%). The top eight pharmacophore models were further tested and had at least a tenfold selectivity against mGluR1 activity (80). Finally, two best pharmacophore models with four pharmacophoric features were selected, to perform screening for a library of commercially available compounds.…”

Section: Pharmacophore-based Virtual Screeningmentioning

confidence: 99%

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Feng

et al. 2015

AAPS J

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Abstract. Allosteric modulators of G protein-coupled receptors (GPCRs), which target at allosteric sites, have significant advantages against the corresponding orthosteric compounds including higher selectivity, improved chemical tractability or physicochemical properties, and reduced risk of receptor oversensitization. Bitopic ligands of GPCRs target both orthosteric and allosteric sites. Bitopic ligands can improve binding affinity, enhance subtype selectivity, stabilize receptors, and reduce side effects. Discovering allosteric modulators or bitopic ligands for GPCRs has become an emerging research area, in which the design of allosteric modulators is a key step in the detection of bitopic ligands. Radioligand binding and functional assays ([ 35 S]GTPγS and ERK1/2 phosphorylation) are used to test the effects for potential modulators or bitopic ligands. High-throughput screening (HTS) in combination with disulfide trapping and fragment-based screening are used to aid the discovery of the allosteric modulators or bitopic ligands of GPCRs. When used alone, these methods are costly and can often result in too many potential drug targets, including false positives. Alternatively, low-cost and efficient computational approaches are useful in drug discovery of novel allosteric modulators and bitopic ligands to help refine the number of targets and reduce the false-positive rates. This review summarizes the state-of-the-art computational methods for the discovery of modulators and bitopic ligands. The challenges and opportunities for future drug discovery are also discussed.

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Section: Pharmacophore-based Virtual Screeningmentioning

confidence: 99%

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Feng

et al. 2015

AAPS J

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“…Brief surveys of both N -alkyl and N -aryl and heteroaryl substituents, including several congeners related to those previously described (Table 1–3), were unsuccessful in identifying favorable starting points and led to modulators which were either inactive or weak PAMs (EC 50 > 10 μM). Interestingly, a related more rigid, acetylene tetralone scaffold recently reported by Merz Pharmaceuticals GmbH 51 displays a similar array of HBA moieties and was reported to have excellent PAM activity (EC 50 < 100 nM) in a recombinant CHO cell line expressing human mGlu 5 .…”

Section: Resultsmentioning

confidence: 99%

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

et al. 2014

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Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure–activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

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“…Additionally, in rodents, the administration of mGluR 5 NAMs reduced the extent of nigrostriatal toxicity in rodents in response to MPTP [146,147], 6-OHDA [148,149], and methamphetamine [150], supporting the use of these drug candidates to exert neuroprotective activity and to slow the progression of neurodegeneration in PD. The relevance of pharmacological blockade of these receptors has inspired the researchers to discover antagonists and negative allosteric modulators [151][152][153][154][155][156][157][158][159][160][161][162][163][164] targeting mGluR 5 .…”

Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

et al. 2017

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Parkinson's Disease (PD) is a long-term neurodegenative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti-parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated to long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated to dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused in a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure-and ligand-based in silico approaches for the development of small molecules to target these receptors.

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Discovery, synthesis, and structure–activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators

Cited by 12 publications

References 38 publications

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

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Discovery, synthesis, and structure–activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators

Cited by 12 publications

References 38 publications

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

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Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)