Evaluation of (4‐Arylpiperidin‐1‐yl)cyclopentanecarboxamides As High‐Affinity and Long‐Residence‐Time Antagonists for the CCR2 Receptor

Abstract

Animal models suggest that the chemokine ligand 2/CC‐chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure–kinetics relationships (SKRs). Herein we report new findings on the structure–affinity relationships (SARs) and SKRs of the reference compound MK‐0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4‐arylpiperidine group suggest that lipophilic hydrogen‐bond‐accepting substituents at the 3‐position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3‐Br: Ki=2.8 nM, residence time (tres)=243 min; 3‐iPr: Ki=3.6 nM, tres=266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3‐position, can also prolong tres; this was most prominently observed in MK‐0483 (Ki=1.2 nM, tres=724 min) and a close analogue (Ki=7.8 nM) with a short residence time.

Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists

“…This is in line with the observation that replacement of this nitrogen atom with a carbon atom did not significantly affect CCR2 activity (Cai et al, 2013). Moreover, SKR studies on cyclopentane-based CCR2 antagonists (Vilums et al, 2013(Vilums et al, , 2015b revealed that replacement of the methoxy-tetrahydropyran ring with a 5-trifluoro-or 5-Br-substituted 2,3-dihydro-1H-indene ring significantly increased the CCR2 residence time (t = 667 and 714 min) compared with 92 min for MK-0812 (Vilums et al, 2015a) without improving the Ki. Modeling the 5-Br-substituted analog (compound 15a) into the MK-0812 structure revealed an extension of the 5-Br-2,3-dihydro-1H-indene ring toward the main orthosteric binding pocket of TM4 and TM5.…”

Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5

“…Each set consisted of multiple representatives of a small number of structurally related chemotypes developed by the respective discovery program. Note that the original library already contained 21 published Merck CCR2 antagonists and their derivatives [26,[94][95][96][97][98][99] (Fig. S2, Supplemental Table 1).…”

A General C(sp3)–C(sp3) Cross-Coupling of Benzyl Sulfonylhydrazones with Alkyl Boronic Acids

“…The transformation utilizes boronic acids, a widely available building block, and alkyl sulfonylhydrazones, bench-stable solids that are readily prepared from aldehydes or ketones . Since the original report, the method has been widely adopted by industry chemists, demonstrating its practicality. , However, to the best of our knowledge, these reports have focused on cross-coupling of benzylic sulfonylhydrazones with aryl and heteroaryl boronic acids 6 , and a general protocol for coupling alkyl boronic acids 7 to construct sp 3 –sp 3 C–C bonds remains elusive.…”