78348-26-2Relevant articles and documents
Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl-xL Antagonist. 1. Manufacture of the Acid Moiety and Development of Some Key Reactions
Hardouin, Christophe,Baillard, Sandrine,Barière, Fran?ois,Copin, Chloé,Craquelin, Anthony,Janvier, Solenn,Lemaitre, Sylvain,Le Roux, Stéphane,Russo, Olivier,Samson, Sébastien
, p. 652 - 669 (2019/12/24)
Our efforts toward the process development of drug candidate 1 are described in a series of two papers. This manuscript focuses on the synthesis of kilogram quantities of acid precursor 2 to provide batches of material for preclinical studies and first-in
Tricyclic Quinoxalinediones: 5,6-Dihydro-1H-pyrroloquinoxaline-2,3-diones and 6,7-Dihydro-1H,5H-pyridoquinoxaline-2,3-diones as Potent Antagonists for the Glycine Binding Site of the NMDA Receptor
Nagata, Ryu,Tanno, Norihiko,Kodo, Toru,Ae, Nobuyuki,Yamaguchi, Hiroshi,et al.
, p. 3956 - 3968 (2007/10/02)
A series of tricyclic quinoxalinediones, 5,6-dihydro-1H-pyrroloquinoxaline-2,3-diones and 6,7-dihydro-1H,5H-pyridoquinoxaline-2,3-diones, were synthesized and was evaluated for their affinity for the glycine binding site of the NMDA receptor using a -5,7-dichlorokynurenic acid binding assay.The six-membered ring-fused tricyclic quinoxalinedione 18g (Ki = 9.9 nM) displayed high affinity for the glycine site.The anilide derivative 20g (Ki = 2.6 nM) was 4-fold more potent than 18g and as potent as L-689,560, one of the most potent glycineantagonists so far prepared.Although the carboxylic acid derivative of the corresponding five-membered ring-fused tricyclic quinoxalinedione 18e (Ki = 7.3 nM) had affinity comparable to that of 18g, the anilide derivative 20e largely decreased in the affinity in contrast to 20g.Enantiomers 23g, 24g, 25g, and 26g were prepared and tested.Only the S enantiomer 25g (Ki = 0.96 nM) retained the affinity among the anilide derivatives, whereas both enantiomers 23g (Ki = 2.3 nM) and 24g (Ki = 9.6 nM) were active among the carboxylic acid derivatives.The origin of the high affinity of carboxylic acid derivatives such as 18e and 18g would be a charge-charge interaction between the anionic carboxylate residues of the compounds and the cationic proton-donor site in the receptor.
(1S)-1-(Aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: Members of a novel class of very potent κ opioid analgesics
Vecchietti,Clarke,Colle,Giardina,Petrone,Sbacchi
, p. 2624 - 2633 (2007/10/02)
The synthesis and structure-activity relationship (SAR) of a novel class of κ opioid analgesics, 1-(amino-methyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60° was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of κ receptor selectivity was a feature of this novel class of antinociceptive agents (μ/κ ratio from 44 to 950 according to the nature of the basic moiety). A SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 μM/kg sc) and κ ligands (K(i)(κ) ca. 0.20 nM) identified so far.
