Ifenprodil Stereoisomers: Synthesis, Absolute Configuration, and Correlation with Biological Activity

Abstract

Ifenprodil (1) is a potent GluN2B-selective N-methyl-D-aspartate (NMDA) receptor antagonist that is used as a cerebral vasodilator and has been examined in clinical trials for the treatment of drug addiction, idiopathic pulmonary fibrosis, and COVID-19. To correlate biological data with configuration, all four ifenprodil stereoisomers were prepared by diastereoselective reduction and subsequent separation of enantiomers by chiral HPLC. The absolute configuration of ifenprodil stereoisomers was determined by X-ray crystal structure analysis of (1R,2S)-1a and (1S,2S)-1d. GluN2B affinity, ion channel inhibitory activity, and selectivity over α, σ, and 5-HT receptors were evaluated. (1R,2R)-Ifenprodil ((1R,2R)-1c) showed the highest affinity toward GluN2B-NMDA receptors (K i = 5.8 nM) and high inhibition of ion flux in two-electrode voltage clamp experiments (IC 50 = 223 nM). Whereas the configuration did not influence considerably the GluN2B-NMDA receptor binding, (1R)-configuration is crucial for elevated inhibitory activity. (1R,2R)-Configured ifenprodil (1R,2R)-1c exhibited high selectivity for GluN2B-NMDA receptors over adrenergic, serotonergic, and σ 1 receptors.

Phenol—Benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B‐selective N‐methyl‐d‐aspartate receptor antagonists

“…Addition of 10 µM glycine and 10 µM ( S )‐glutamate induced a characteristic NMDA‐specific ion current that was inhibited by the application of 10 µM of 21q , 22d , and 22m . [ 31,46 ] To evaluate the activity of the test compounds, the inhibitory activity of ifenprodil ( 1 ) was also recorded at concentrations of 1 and 10 µM. Compounds achieving more than 80% inhibitory activity at 10 µM were tested at a concentration of 1 µM as well.…”

“…In previous studies, it was shown that ligands with (R)-configuration at the benzylic position represent the eutomers. [36,46] Therefore, (1R,2R)-Ifenprodil [31] 5.8 ± 1.3 Nd 125 ± 24 98 ± 34…”

“…[27][28][29][30] The selectivity profile depends on the relative and absolute configuration of ifenprodil. [31] (2) The bioavailability of ifenprodil is rather low due to fast biotransformation. In particular, fast conjugation of the phenol of ifenprodil (1) with glucuronic acid was detected in in vitro and in vivo experiments.…”

Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74

“…As a derivative of phenylalanine, PF74 is prepared from enantioenriched material from natural sources. Although there is a vast body of literature on strategies to avoid epimerisation during peptide coupling [ 15 ], the inherent asymmetry of biological systems necessitates that control of absolute stereochemical configuration of small molecule inhibitors remains integral to their activity [ 14 , 16 , 17 , 18 ].…”

Negative allosteric modulators of NMDA receptors with GluN2B subunit: Alanine‐derived benzoxazolone bioisosteres of 2‐methyl‐3‐benzazepine‐1,7‐diols

“…[25][26][27][28] It was shown that the selectivity of ifenprodil depends considerably on the configuration of the two centers of chirality. [29] Moreover, the bioavailability of ifenprodil is rather low due to fast biotransformation, in particular rapid glucuronidation of the phenol. [30] To improve selectivity and bioavailability, the 2-amino-1phenylpropanol substructure of ifenprodil (1) and traxoprodil (2) was rearranged in the class of 3-benzazepines 3 (Figure 1).…”