Conformationally Constrained Analogues ofL-Glutamate as Subtype-Selective Modulators of Metabotropic Glutamate Receptors

Ma, Dawei

doi:10.1006/bioo.1998.1107

Cited by 21 publications

(5 citation statements)

References 68 publications

(60 reference statements)

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“…5-Ala-b' is the mGluR antagonist (S)-M4CPG. 10 Hydrolysis without preliminary N-methylation led to competitive formation of the corresponding N-methylhydantoins 6 in moderate yield ( Figure 2c) owing to cyclisation of the urea onto the newly revealed carboxylic acid. These hydantoins 6 could be hydrolysed cleanly to 5 in a second step, but are nonetheless themselves valuable target structures.…”

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confidence: 99%

Asymmetric α-arylation of amino acids

Leonard

Ward

Clayden

2018

Nature

111

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Quaternary amino acids, in which the -carbon bearing the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds. 1,2 In contrast to enantioselective alkylation at this −carbon, for which there are several methods, 3-8 general enantioselective introduction of an aryl substituent at the -carbon is synthetically challenging. 9 Nonetheless, the product aryl amino acids and their derivatives have proved valuable as precursors to bioactive molecules. 10,11 Here we describe the synthesis of quaternary -aryl amino acids from enantiopure amino acid precursors by -arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N'-arylurea adduct 12 of an imidazolidinone derivative 6 of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of high-value transition metals, and allows arylation with electron-rich, electron-poor, and heterocyclic substituents. Either enantiomer of the product may be formed from a single amino acid precursor. The method is practical and scalable, providing the opportunity to produce -arylated quaternary amino acids in multi-gram quantities.

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confidence: 99%

Asymmetric α-arylation of amino acids

Leonard

Ward

Clayden

2018

Nature

111

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“…Taking point in Glu as lead, − incorporation of a cyclopropane ring in the 3,4-position of the Glu scaffold has been explored to give four diastereomers l -2-(carboxycyclopropyl)glycine ( l -CCG-I–IV) . Notably, analogue (2 S ,3 S ,4 S )-2-(2-carboxycyclopropyl)glycine ( l -CCG-I, Figure ) was found to be a selective agonist for mGlu receptors with a preference for group II. , In contrast, l -CCG-II is only a weak agonist at the mGlu receptors with an EC 50 value of 300 μM at mGlu 2 .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu₂ Receptor Agonist

Liu,

Eshak,

Malhaire

et al. 2024

J. Med. Chem.

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Metabotropic glutamate (Glu) receptors (mGlu receptors) play a key role in modulating excitatory neurotransmission in the central nervous system (CNS). In this study, we report the structure-based design and pharmacological evaluation of densely functionalized, conformationally restricted glutamate analogue (1S,2S,3S)-2-((S)-amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic acid (LBG30300). LBG30300 was synthesized in a stereocontrolled fashion in nine steps from a commercially available optically active epoxide. Functional characterization of all eight mGlu receptor subtypes showed that LBG30300 is a picomolar agonist at mGlu 2 with excellent selectivity over mGlu 3 and the other six mGlu receptor subtypes. Bioavailability studies on mice (IV administration) confirm CNS exposure, and an in silico study predicts a binding mode of LBG30300 which induces a flipping of Tyr144 to allow for a salt bridge interaction of the acetate group with Arg271. The Tyr144 residue now prevents Arg271 from interacting with Asp146, which is a residue of differentiation between mGlu 2 and mGlu 3 and thus could explain the observed subtype selectivity.

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“…Over decades, numerous phosphonate analogs of amino acids have been synthesized and found application in both organic and medicinal chemistry, including the preparation of more complex compounds ( Figure 3 ). For example, 3-aminopropylphosphonic acid 13 (3-APPA) is an agonist of GABA B receptor [ 23 ], while L-2-amino-4-phosphonobutyric acid 14 (L-AP4) was found to be a selective group III metabotropic glutamate receptor agonist that acts at mGlu4, mGlu8, mGlu6, and mGlu7 receptors [ 24 ]. Compounds 15 have been designed as phosphonate analogs of homoserine, an important amino acid involved in physiologically relevant transformation [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Enantiomerically Enriched Protected 2-Amino-, 2,3-Diamino- and 2-Amino-3-Hydroxypropylphosphonates

2023

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Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have been developed starting from, respectively, N-protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl (R)- and (S)-2-(N-Boc-amino)propylphosphonates were obtained via direct regiospecific hydrogenolysis of the respective enantiomer of (R)- and (S)-N-Boc-(aziridin-2-yl)methylphosphonates. N-Boc-protected (R)- and (S)-2,3-diaminopropylphosphonates were synthesized from (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates via a regiospecific ring-opening reaction with neat trimethylsilyl azide and subsequent reduction of (R)- and (S)-2-(N-Boc-amino)-3-azidopropylphosphonates using triphenylphosphine. On the other hand, treatment of the corresponding (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates with glacial acetic acid led regiospecifically to the formation of (R)- and (S)-2-(N-Bn-amino)-3-acetoxypropylphosphonates.

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Conformationally Constrained Analogues ofL-Glutamate as Subtype-Selective Modulators of Metabotropic Glutamate Receptors

Cited by 21 publications

References 68 publications

Asymmetric α-arylation of amino acids

Asymmetric α-arylation of amino acids

Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu₂ Receptor Agonist

Synthesis of Enantiomerically Enriched Protected 2-Amino-, 2,3-Diamino- and 2-Amino-3-Hydroxypropylphosphonates

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Conformationally Constrained Analogues ofL-Glutamate as Subtype-Selective Modulators of Metabotropic Glutamate Receptors

Cited by 21 publications

References 68 publications

Asymmetric α-arylation of amino acids

Asymmetric α-arylation of amino acids

Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu2 Receptor Agonist

Synthesis of Enantiomerically Enriched Protected 2-Amino-, 2,3-Diamino- and 2-Amino-3-Hydroxypropylphosphonates

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Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu₂ Receptor Agonist