3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts

Brnardic, Edward J.; Fraley, Mark E.; Garbaccio, R. M.; Layton, M. E.; Sanders, John M.; Culberson, Charles H.; Jacobson, Marlene A.; Magliaro, Brian C.; Hutson, Pete H.; O’Brien, Julie A.; Huszar, Sarah L.; Uslaner, Jason M.; Fillgrove, Kerry L.; Tang, Cuyue; Kuo, Yuhsin; Sur, Sylvie M.; Hartman, George D.

doi:10.1016/j.bmcl.2010.03.089

Cited by 41 publications

(23 citation statements)

References 19 publications

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“…Although several novel types of positive allosteric modulators have been discovered (XII-XVI in Table 8) (Zhang et al, 2008b;Duplantier et al, 2009;Brnardic et al, 2010;Cid et al, 2010;D'Alessandro et al, 2010;Tresadern et al, 2010), only few negative allosteric modulators of group II mGlu receptors are known. For two non-amino acid-based classes of group II antagonists Wichmann et al, 1999), it has not been clearly established whether they are competitive or allosteric.…”

Section: Allosteric Modulation Of Family C Gpcrsmentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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Section: Allosteric Modulation Of Family C Gpcrsmentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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“…A representative example from this series is compound 39 with EC 50 value of 82 nM in a FLIPR assay. The hit-to-lead optimization of this oxazolidinone series is reported in a separate literature [86]. Compound 39 was shown to be brain penetrant and able to attenuate ketamine-induced psychomotor activity in rats similar to an mGluR2/3 agonist, an assay sensitive to clinically therapeutic antipsychotics (Figure 7).…”

Section: Isoindolonesmentioning

confidence: 99%

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

Szabó¹,

Keserü²

2014

CTMC

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This review summarizes drug discovery efforts on mGluR2 positive allosteric modulators IntroductionGlutamate is the major excitatory neurotransmitter that plays a role in eliciting and modulating synaptic responses. These processes involve ionotropic (AMPA, NMDA, kainate) and metabotropic receptors. Up to now eight metabotropic glutamate (mGluR) receptors have been described and characterized [1] and were classified into three subgroups based on their similarity in sequence, signaling and pharmacology [2]. Most of the drug discovery interest has been focused to Group I and Group II targets that include mGluR1/mGluR5 and mGluR2/mGluR3 receptors, respectively. Inhibition of mGluR1 receptors has been connected to anxiolytic [3] and analgesic [4] effects. Negative modulation of mGluR5 receptors found to be beneficial in the animal models of anxiety, depression, Fragile-X and autism spectrum disorder (ASD) [5,6]. mGluR5 positive allosteric modulators (PAMs) are believed to be attractive as a potential pharmacotherapy of schizophrenia [7]. In addition to mGluR5 PAMs compounds targeting Group II receptors are also considered as a promising treatment option for schizophrenia. mGluR2 and mGluR3 receptors impact the glutamatergic transmission in certain brain areas implicated in the pathophysiology of schizophrenia. These neurobiological observations have been validated in the experimental models of schizophrenia indicating that Group II mGluR agonists are effective in a number of antipsychotic animal models [8][9][10][11]. One of the best characterized compounds from this class is the mGluR2/3 receptor agonists LY404039 that showed remarkable efficacy in animal

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“…The formed alkoxide can then add on the cumulene and a SN 2 ring closure finally gives the heterocycles. More recently, the methodology has been used in the synthesis of libraries of bioactive compounds [154][155] and the first example involving isoselenocyanates has been reported. [156] Scheme 7.24: Halide salt-catalyzed formal cycloaddition of epoxides and cumulenes.…”

Section: Formal [3+2] Cycloadditions With Cumulenesmentioning

confidence: 99%

Synthesis of Saturated Heterocycles via Metal-Catalyzed Formal Cycloaddition Reactions That Generate a C–N or C–O Bond

Waser

2013

Topics in Heterocyclic Chemistry

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In this section, the synthesis of saturated N-and O-heterocycles via formal cycloaddition is presented. The main focus is on metal-catalyzed reactions involving C-C or C-X  bond cleavage in three-or four-membered rings. After a fast presentation of pioneering works, the important breakthroughs of the last two decades are presented. The section starts with reactions involving three-membered rings. Formal [3+2] cycloadditions of donor-acceptor-substituted cyclopropanes and methylenecyclopropanes with carbonyls and imines are important methods to access tetrahydrofuran and pyrrolidine heterocycles. Formal [3+3] cycloadditions have emerged more recently. On the other hand, reactions of epoxides and aziridines with carbon monoxide or cumulenes are now well-established method to access heterocycles. These processes have been completed more recently with cycloaddition with olefins, carbonyls and imines. The section ends with the emerging field of four-membered ring activation for cycloaddition with  systems. This is the peer reviewed version of the following article: Top. Heterocycl. Chem. 2013, 32, 225, which The discovery of classical cycloaddition reactions, such as the (hetero) DielsAlder and 1,3-dipolar cycloadditions, has contributed tremendously to a more efficient access towards both carbocycles and heterocycles. The introduction of the term cycloaddition was necessary to distinguish these new types of reactions from previously discovered processes leading to cyclic structures, such as the famous Robinson annulation. In principle, each cycloaddition can be considered as a special case of the more general annulation process, but from which point on an annulation can be called a cycloaddition has been the topic of intensive discussions for decades, and is still not settled today. In 1968, Huisgen proposed a set of rules for the definition of cycloaddition, and the two first are still largely recognized as prerequisite: Although the rule that all the atoms of the starting materials have to be included in the product is not explicitly included in the definition, this requirement is usually recognized by most organic chemists. Even if electrocyclic cyclization processes were included in the original definition of Huisgen, the term cycloaddition is mostly used today for those reactions proceeding via the formation of at least two new bonds. Nevertheless, several researchers think that the term cycloaddition should be more strictly limited to reactions involving a continuous overlap of  electrons, and consequently allowing a concerted process. In fact, in his seminal publication, Huisgen already introduced further rules, in particular rule number 3, which explicitly stated that cycloadditions should not involve the cleavage of sigma bonds: -Huisgen Rule 3: "Cycloadditions do not involve the cleavage of  bonds." Unfortunately, in the same publication, Huisgen also described several reactions proceeding via -bond cleavage as cycloaddition. To solve this definition dilemma, several researchers have used th...

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3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts

Cited by 41 publications

References 19 publications

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

Synthesis of Saturated Heterocycles via Metal-Catalyzed Formal Cycloaddition Reactions That Generate a C–N or C–O Bond

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