Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold

Thum, Simone; Kokornaczyk, Artur K.; Seki, Tomoaki; Maria, Monica De; Zacarı́as, Natalia V. Ortiz; Vries, Henk de; Weiss, Christina; Koch, Michael; Schepmann, Dirk; Kitamura, Masato; Tschammer, Nuška; Heitman, Laura H.; Junker, Anna; Wünsch, Bernhard

doi:10.1016/j.ejmech.2017.04.046

Cited by 14 publications

(16 citation statements)

References 19 publications

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“…For this assay, we also included the intracellular ligands CCR2-RA-[ R ], SD-24 and JNJ-27141491, as well as the CCR2/CCR5 orthosteric antagonist TAK-779 as a positive control (Figure 1), since it is a potent CCR5 antagonist in a variety of functional assays. 26,27…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5

et al. 2019

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CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolopyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure–affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited β-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5

et al. 2019

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“…In a recent study, Wünsch and colleagues discovered the first probe dependent CCR5 PAM. 241 Through an innovative bioluminescence resonance energy transfer (BRET)-cAMP assay, the endogenous agonists CCL4 and CCL5 were screened at CCR2 and CCR5. Chemical modifications and resulting SAR were performed on a 2-benzazapine scaffold showing a sensitive 7-position where the addition of p -tolyl moiety led to a chemical switch toward CCR2 modulation without CCR5 activity.…”

Section: Recent Advances In the Discovery And Design Of Class A Gpcr mentioning

confidence: 99%

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

Wold

Chen²,

Cunningham³

et al. 2018

J. Med. Chem.

124

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G-protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented, and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials. Numerous class A GPCR allosteric modulators have been discovered recently, and emerging trends such as the availability of GPCR crystal structures, diverse functional assays, and structure-based computational approaches are improving optimization and development. This Perspective provides an update on allosterically targeted class A GPCRs and their disease indications and the medicinal chemistry approaches toward novel allosteric modulators and highlights emerging trends and opportunities in the field.

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“… 11 Later approaches to find CCR5 ligands used homology models of the CCR5 receptor 12 , 13 and ligand-based fragment merging. 14 In 2013, a crystal structure of CCR5 bound to MVC (Protein Data Bank (PDB): 4MBS) 15 was published, providing a structural basis for the virtual discovery of CCR5 ligands of previously undescribed chemotypes. Maraviroc binds to an allosteric, and not orthosteric, binding site of the CCR5 receptor.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel CCR5 Ligands as Anticolorectal Cancer Agents by Sequential Virtual Screening

et al. 2021

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C-C chemokine receptor type 5 (CCR5) is a member of the G protein-coupled receptor. CCR5 and its interaction with chemokine ligands have been crucial for understanding and tackling human immunodeficiency virus (HIV)-1 entry into target cells. In recent years, the change in CCR5 expression has been related to the progression of different cancer types. Patients treated with the CCR5 ligand, maraviroc (MVC), showed a deceleration in tumor development especially for metastatic colorectal cancer. Based on the crystal structure of CCR5, we herein describe a multistage virtual screening protocol including pharmacophore screening, molecular docking, and protein–ligand interaction fingerprint (PLIF) postdocking filtration for discovery of novel CCR5 ligands. The applied virtual screening protocol led to the identification of four hits with binding modes showing access to the major and minor pockets of the MVC binding site. Compounds 2 – 4 showed a decrease in cellular proliferation upon testing on the metastatic colorectal cancer cell line, SW620, displaying 12, 16, and 4 times higher potency compared to MVC, respectively. Compound 3 induced apoptosis by arresting cells in the G0/G1 phase of the cell cycle similar to MVC. Further in vitro assays showed compound 3 drastically decreasing the CCR5 expression and cellular migration 48 h post treatment, indicating its ability to inhibit metastatic activity in SW620 cells. The discovered hits represent potential leads for the development of novel classes of anticolorectal cancer agents targeting CCR5.

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Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold

Cited by 14 publications

References 19 publications

Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5

Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

Discovery of Novel CCR5 Ligands as Anticolorectal Cancer Agents by Sequential Virtual Screening

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