864682-69-9Relevant academic research and scientific papers
Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites
Selvam, Chelliah,Lemasson, Isabelle A.,Brabet, Isabelle,Oueslati, Nadia,Karaman, Berin,Cabaye, Alexandre,Tora, Amélie S.,Commare, Bruno,Courtiol, Tiphanie,Cesarini, Sara,McCort-Tranchepain, Isabelle,Rigault, Delphine,Mony, Laetitia,Bessiron, Thomas,McLean, Heather,Leroux, Frédéric R.,Colobert, Fran?oise,Daniel, Hervé,Goupil-Lamy, Anne,Bertrand, Hugues-Olivier,Goudet, Cyril,Pin, Jean-Philippe,Acher, Francine C.
, p. 1969 - 1989 (2018/03/21)
A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.
Determination of the absolute configuration of phosphinic analogues of glutamate
Commare, Bruno,Rigault, Delphine,Lemasson, Isabelle A.,Deschamps, Patrick,Tomas, Alain,Roussel, Pascal,Brabet, Isabelle,Goudet, Cyril,Pin, Jean-Philippe,Leroux, Frdric R.,Colobert, Franoise,Acher, Francine C.
supporting information, p. 1106 - 1112 (2015/03/03)
A series of phosphinic glutamate derivatives (e.g.LSP1-2111) have been proven to be potent agonists of metabotropic glutamate (mGlu) receptors and shown promising in vivo activity. However, so far all were synthesized and tested as a mixture of two diaste
Qualification of LSP1-2111 as a brain penetrant group III metabotropic glutamate receptor orthosteric agonist
Cajina, Manuel,Nattini, Megan,Song, Dekun,Smagin, Gennady,Jorgensen, Erling B.,Chandrasena, Gamini,Bundgaard, Christoffer,Toft, Dorthe Bach,Huang, Xinyan,Acher, Francine,Doller, Dario
supporting information, p. 119 - 123 (2014/03/21)
LSP1-2111 is a group III metabotropic glutamate receptor agonist with preference toward the mGlu4 receptor subtype. This compound has been extensively used as a tool to explore the pharmacology of mGlu4 receptor activation in preclinical animal behavioral
DIASTEREOISOMERS OF HYPOPHOSPHOROUS ACID DERIVATIVES
-
Page/Page column 2-3, (2010/10/03)
The invention relates to the diastereoisomers of hypophosphorous acid derivatives, having formula (I), wherein the phenyl group is substituted by one or several atoms or groups, occupying one or several positions on the phenyl ring, and a method for the s
THIOPHOSPHI(O)NIC ACID DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
-
Page/Page column 10; 13-14, (2010/06/16)
The invention relates to thiophosphi(o)nic acid derivatives having formula (I) wherein. M is a [C(R3,R4)]n1-C(E,COOR1,N(H,Z)) group, or an optionally substituted Ar—CH(COOR1,N(H,Z)) group (Ar designating an aryl
A virtual screening hit reveals new possibilities for developing group III metabotropic glutamate receptor agonists
Selvam, Chelliah,Oueslati, Nadia,Lemasson, Isabelle A.,Brabet, Isabelle,Rigault, Delphine,Courtiol, Tiphanie,Cesarini, Sara,Triballeau, Nicolas,Bertrand, Hugues-Olivier,Goudet, Cyril,Pin, Jean-Philippe,Acher, Francine C.
experimental part, p. 2797 - 2813 (2010/08/06)
(R)-PCEP (3-amino-3-carboxypropyl-2′-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and
Hypophosphorous Acid Derivatives and their Therapeutical Applications
-
Page/Page column 15, (2009/07/17)
Hypophosphorous acid derivatives having Formula (I) wherein .M is a [C(R3,R4)]n1-C(E,COOR1,N(H,Z)) group, or an optionally substituted Ar—CH(COOR1,N(H,Z)) group, or an a, β, or a β, g-cyclic amino acid; .R1 is H or R, R being an hydroxy or a ca
L-(+)-2-amino-4-thiophosphonobutyric acid (L-thioAP4), a new potent agonist of group III metabotropic glutamate receptors: Increased distal acidity affords enhanced potency
Selvam, Chelliah,Goudet, Cyril,Oueslati, Nadia,Pin, Jean-Philippe,Acher, Francine C.
, p. 4656 - 4664 (2008/03/12)
L-2-Amino-4-phosphonobutyric acid (L-AP4), L-2-amino-4-thiophosphonobutyric acid (L-thioAP4), and L-2-amino-4-(hydroxy)phosphinylbutyric acid (desmethylphosphinothricin, DMPT) were synthesized from protected vinylglycine. They were tested as agonists at g
Prodrug forms of N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-γ- [ψP(O)(OH)]-glutarate, a potent inhibitor of folylpoly-γ-glutamate synthetase: Synthesis and hydrolytic stability
Feng, Yan,Coward, James K.
, p. 770 - 788 (2007/10/03)
Ester prodrugs of the phosphinate pseudopeptide N-[(4-deoxy-4-amino-10- methyl)pteroyl]glutamate-γ-[ψP-(O)(OH)]-glutarate (1a) were synthesized. H-phosphinic acids derived from N-Cbz vinyl glycine esters were converted to the desired pseudopeptides by Michael addition to α-methyleneglutarate esters. Pivaloyloxymethyl (POM) ester moieties were incorporated in both the N-terminal and C-terminal fragments prior to formation of either C-P bond, N-Alkylation of the corresponding amides derived from N-(N-methyl)aminobenzoic acid with 2,4-diamino-6-(bromomethyl)pteridine gave the target compounds. POM esters of methotrexate and the corresponding γ-glutamyl conjugate were also synthesized using the same strategy. All prodrugs were evaluated in Chinese hamster ovary cells. Although the pseudopeptide prodrugs were ineffective, prodrugs of methotrexate and the corresponding γ-glutamyl conjugate were equipotent with the parent compounds. Stability of the prodrugs was investigated in both phosphate buffer and cell line medium to provide a rationale for the observed biological data.
A stereoselective synthesis of phosphinic acid phosphapeptides corresponding to glutamyl-γ-glutamate and incorporation into potent inhibitors of folylpoly-γ-glutamyl synthetase
Hartley, David M.,Coward, James K.
, p. 6757 - 6774 (2007/10/03)
Radical addition of H3PO2 to N-/C-protected vinyl glycine led to the corresponding H-phosphinic acid in excellent yield. The non-nucleophilic H-phosphinic acid was converted to a nucleophilic P III species, RP(OTMS)2, which was used in two approaches to the target phosphinic acid containing pseudopeptide. New methodology was developed that led to excellent yields in the reaction of RP(OTMS)2 with unactivated electrophiles, including an acyclic homoallylic bromide. However, en route to the target pseudopeptide, Arbuzov reaction of RP(OTMS) 2 with a cyclic homoallylic bromide, (R)-3-(bromomethyl)-cyclopent-1- ene, led to a rearranged allylic phosphinic acid rather than the desired homoallylic derivative, a putative glutarate surrogate. Conjugate addition of RP(OTMS)2 to α-methylene glutarate containing a chiral auxiliary resulted in only modest diastereoselectivity. Purification by flash chromatography provided protected derivatives of both diastereomers of the pseudopeptide. Following global deprotection, coupling of (S)-H-Glu-γ- [Ψ(P(O)(OH)(CH2))]-(S)-Glu-OH and (S)-H-Glu-γ-[Ψ(P(O) (OH)(CH2))]-(R)-Glu-OH to (4-amino-4-deoxy-10-methyl)pteroyl azide led to the target compounds for biochemical study as inhibitors of the ATP-dependent ligase, folylpoly-γ-glutamate synthetase.
