Structure–Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

Abstract

Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist

“…24 The 3-carboxylic acid functionality was displaced with a phosphonic acid group, compound 1c (Figure 2), which led to a significant reduction in binding affinity at the iGluRs (Table 1). 24 …”

“…Based on synthetic tractability, the following seven analogs were thus designed: 3-chloro ( 1d ), 3-trifluoromethyl ( 1e ), 3-amino ( 1f ), 3-cyano ( 1g ), 3-carbamido ( 1h ), 3-boronic acid ( 1i ), and 3,4-dihydroxy ( 1j ). The synthesis of 1d-j was carried out by a stereoselective rhodium(I)-catalyzed addition of an arylboronic acid to protected enone 2 24 as the key step (Scheme 1). 25 Hereby, the 2,3- trans stereochemistry on the proline ring was set, and subsequent functional group transformations in accordance with earlier reported strategies ( 1d-f ; Scheme 2), ( 1g,h ; Scheme 3), ( 1i ;Scheme 4) and ( 1j ; Scheme 5), gave the free amino acids 1d-j ready for pharmacological evaluation.…”

“…25 Hereby, the 2,3- trans stereochemistry on the proline ring was set, and subsequent functional group transformations in accordance with earlier reported strategies ( 1d-f ; Scheme 2), ( 1g,h ; Scheme 3), ( 1i ;Scheme 4) and ( 1j ; Scheme 5), gave the free amino acids 1d-j ready for pharmacological evaluation. 23,24 …”

“…Subsequent functional group transformations to obtain the free amino acids 1k-m followed the strategy for comparable analogs previously reported by us. 23,24 …”

Recent Progress in Metal Catalyzed Direct Carboxylation of Aryl Halides and Pseudo Halides Employing CO2: Opportunities for 11C Radiochemistry

“…Aryl carboxylic acids are an important class of compounds and are used in a variety of medicinal chemistry targets and have also been used as radiolabeled tracers for imaging with positron emission tomography (PET). For example, small molecules containing aryl carboxylic acids are used as ionotropic glutamate receptor (iGluR) antagonist, mycobacterium protein tyrosine phosphatase inhibitor, selective dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A) inhibitor, chloride channel blocker, peroxisome proliferator‐activated receptor gamma (PPARγ) agonists, and angiotensin II receptor agonist …”