Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators

Kubas, Holger; Meyer, Udo; Hechenberger, Mirko; Klein, Kai-Uwe; Plitt, Patrick; Spexgoor, Harm W.; Assema, S.G.A. van; Abel, Ulrich

doi:10.1016/j.bmcl.2013.09.059

Cited by 12 publications

(3 citation statements)

References 16 publications

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“…8) Gastambide et al, 2012Gastambide et al, , 2013Gilmour et al, 2013. 9) Gantois et al, 2013;Harvey et al, 2013;Kubas et al, 2013;Stocchi et al, 2013;Doré et al, 2014;Vranesic et al, 2014;de Esch et al, 2015;Reilmann et al, 2015;Kumar et al, 2016;Rouzade-Dominguez et al, 2017;Westmark et al, 2018. 10) Rodriguez et al, 2005Hammond et al, 2010;.…”

Section: Group I Pams Nams Nalsunclassified

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

Gregory

Goudet

2020

Pharmacol Rev

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Section: Group I Pams Nams Nalsunclassified

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

Gregory

Goudet

2020

Pharmacol Rev

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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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“…Carbocyclic or heterocyclic scaffolds constitute the basic skeleton of numerous bioactive compounds and pharmaceutical products . Hexahydrocyclopentapyrrolone (Figure ) derivatives represent an essential pharmacophore for diversified pharmacological activities such as antibacterial agents, autotaxin inhibitors, α4β2 inhibitors, CCR5 antagonist, DPP-IV inhibitors, FAAH inhibitors, Glutamate receptor modulators, HSP90 inhibitors, JAK inhibitors, c-MET protein kinase inhibitors, Retinol binding protein-4 antagonist, and Type-1 glycine transporter (GlyT1) inhibitors …”

Section: Introductionmentioning

confidence: 99%

An Efficient and Scalable Synthesis of tert-Butyl (3aR,6aS)-5-Oxohexahydrocyclo penta[c]pyrrole-2(1H)-carboxylate: A Pharmacologically Important Intermediate

Bahekar

Jadav

Goswami

et al. 2017

Org. Process Res. Dev.

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Hexahydrocyclopentapyrrolone derivatives constitute an important class of bicycles, and it represents an essential pharmacophore for diversified pharmacological activities. A highly efficient process for the synthesis of tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 1 has been developed. The improved process involves transformation of isoindole 4 to diacid 5, using an inexpensive KMnO 4 mediated oxidative cleavage as a key step. The developed process was cost-effective, high yielding, kilogram scalable, and commercially viable for synthesis of 1.

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Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators

Cited by 12 publications

References 16 publications

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

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

An Efficient and Scalable Synthesis of tert-Butyl (3aR,6aS)-5-Oxohexahydrocyclo penta[c]pyrrole-2(1H)-carboxylate: A Pharmacologically Important Intermediate

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