Discovery and structure–activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators

Zhou, Hao; Topiol, Sidney W.; Grenon, Michel; Jimenez, Hermogenes N.; Uberti, Michelle A.; Smith, Daniel G.; Brodbeck, Robbin; Chandrasena, Gamini; Pedersen, Henrik; Madsen, Jens Christian; Doller, Darı́o; Li, Guiying

doi:10.1016/j.bmcl.2012.12.078

Cited by 9 publications

(2 citation statements)

References 24 publications

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“…As an initial in vivo evaluation of 25 , we undertook a murine study in a marble burying paradigm, a model which has been used to probe the antianxiolytic effect of mGlu 5 NAMs. , In brief, 24 marbles were evenly spaced across the surface of sawdust bedding, and male CD-1 mice treated orally with vehicle (10% Solutol HS15, 90% (10% aqueous (2-hydroxypropyl)-β-cyclodextrin)) or 25 (1, 3, 10, or 30 mg/kg) 30 min before the start of the test. After pretreatment, mice were placed individually in a cage containing the marbles, and after 30 min mice were removed and the number of marbles buried by at least two-thirds into the sawdust were counted.…”

Section: Resultsmentioning

confidence: 99%

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu₅ Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

et al. 2015

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Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.

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Section: Resultsmentioning

confidence: 99%

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu₅ Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

et al. 2015

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“…Spirooxazoline and spirooxazine scaffolds are useful structural motifs in many biologically active molecules . Thus, development of synthetic methodologies for their derivatives has attracted great interest from synthetic chemists for years.…”

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confidence: 99%

Anti-Diastereoselective Synthesis of CF₃-Containing Spirooxazolines and Spirooxazines via Regiospecific Trifluoromethylative Spirocyclization by Photoredox Catalysis

et al. 2015

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A novel synthesis of CF3-containing spirooxazolines and spirooxazines has been developed. Regiospecific trifluoromethylative spirocyclization (CF3-spirocyclization) of cyclic alkenes bearing an amide pendant mediated by photoredox catalysis is a useful strategy for construction of a C(sp(3))-CF3 bond and an spirooxazoline or spirooxazine ring onto C═C bonds via a single step. The key intermediate is α-CF3-substituted carbocationic species smoothly generated from single-electron-transfer (SET) photoredox processes, which results in diastereoselective spirocyclization. This is the first example of synthesis of CF3-containing spirooxazolines and spirooxazines in anti-fashion with respect to the CF3 group and the oxygen atom of the spirocycles.

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Spirooxazoline Synthesis by an Oxidative Dearomatizing Cyclization

Tariq

Moran

2020

Eur J Org Chem

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Spirocyclic compounds are of increasing importance owing to their potential applications in the development of new pharmaceuticals. Herein, we describe a new, rapid access to rarely seen spirooxazolines utilizing an I(I)/I(III) reaction manifold. The scope of the cyclization using phenols and naphthols is described along with the stereoselective functionalization of the spirocycles. The application of this method to the formation of dihydrooxazines is also demonstrated.

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Discovery and structure–activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators

Cited by 9 publications

References 24 publications

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu₅ Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu₅ Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

Anti-Diastereoselective Synthesis of CF₃-Containing Spirooxazolines and Spirooxazines via Regiospecific Trifluoromethylative Spirocyclization by Photoredox Catalysis

Spirooxazoline Synthesis by an Oxidative Dearomatizing Cyclization

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Discovery and structure–activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators

Cited by 9 publications

References 24 publications

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

Anti-Diastereoselective Synthesis of CF3-Containing Spirooxazolines and Spirooxazines via Regiospecific Trifluoromethylative Spirocyclization by Photoredox Catalysis

Spirooxazoline Synthesis by an Oxidative Dearomatizing Cyclization

Contact Info

Product

Resources

About

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu₅ Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu₅ Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

Anti-Diastereoselective Synthesis of CF₃-Containing Spirooxazolines and Spirooxazines via Regiospecific Trifluoromethylative Spirocyclization by Photoredox Catalysis