The design and synthesis of novel, potent and orally bioavailable N-aryl piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity

Cumming, John G.; Bower, Justin; Waterson, David; Faull, Alan W.; Poyser, Philip J.; Turner, Peter G.; McDermott, Benjamin P.; Campbell, Andrew D.; Hudson, Julian A.; James, Michael J.; Winter, Jon; Wood, Christine

doi:10.1016/j.bmcl.2012.04.118

Cited by 17 publications

(16 citation statements)

References 24 publications

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“…163 US28 ligands include compounds 45 , 180 46 , 47 , 181 48 , 182 49 , 181 50 , 184 51 , 185 and 52 . 186 CCR2 ligands include compounds 53 , 173 54 , 174 55 , 175 56 , 177 57 , 58 , 45 59 , 178 and CCR9 ligands 60 . 179 Interactions between the ligands and specific residues derived from X-ray structures (bold), mutation studies (gray), or models without support from experimental data (gray italics) are depicted by a dotted line, interacting groups are surrounded by a dotted line, and key features are summarized by a solid box.…”

Section: Crystal Structure-based Analysis Of the Effects Of Site-dirementioning

confidence: 99%

“…Y120 3.32 A, H121 3.33 , and T292 7.40 A mutations resulted in significant decrease of binding of ligands 19 , 19 – 1 , 25 , 26 , and 27 , 52 indicating that (at least parts of) these ligands occupy the minor pocket. SAR studies show the importance of hydrophobic interactions (increased affinity for more apolar substituents in chemical series around 54 , 174 55 , 175 and 57 / 58 45 ) and steric and conformational compatibility (decreased affinity for 2-chlorine substituted analogues of 53 (173) and 54 (174)) with the minor and/or major hydrophobic binding pocket of CCR2. SAR studies indicate that the stereochemistry of trisubstituted cyclohexane of 57 is important for CCR2 affinity, 45 in line with the tight packing of the corresponding cyclohexane ring of 58 against W98 2.60 in the CCR2 crystal structure (Figure 5).…”

Section: Crystal Structure-based Analysis Cxcr4 Ccr2 Ccr5 Ccr9 Anmentioning

confidence: 99%

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Structural Analysis of Chemokine Receptor–Ligand Interactions

et al. 2017

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This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure–activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor–ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors.

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Section: Crystal Structure-based Analysis Of the Effects Of Site-dirementioning

confidence: 99%

Section: Crystal Structure-based Analysis Cxcr4 Ccr2 Ccr5 Ccr9 Anmentioning

confidence: 99%

Structural Analysis of Chemokine Receptor–Ligand Interactions

et al. 2017

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“…Preclinical studies have shown possible utility for small molecule blockade of CCR2, a G‐protein‐coupled receptor which binds MCP‐1, a major chemoattractant for monocytes and T cells. Thus, CCR2 antagonists may also be useful therapeutic agents in treating autoimmune diseases in which chemokine signalling plays a role . Studies which have synthesized novel compounds have identified side chains that are able to block CCR2 activity when added to a lead compound.…”

Section: Novel Drug Targetsmentioning

confidence: 99%

“…Studies which have synthesized novel compounds have identified side chains that are able to block CCR2 activity when added to a lead compound. These motifs are N ‐alkylated piperazine and piperidine, which are closely related structurally (Figure a) . Because enaminone E121 was demonstrated to be efficacious in decreasing pro‐inflammatory mediators both in vitro and in vivo , a new series of compounds (JODI) was created by incorporating the N ‐alkylated piperazine motif into the existing E121 pharmacophore (Figure b).…”

Section: Novel Drug Targetsmentioning

confidence: 99%

Current and novel anti-inflammatory drug targets for inhibition of cytokines and leucocyte recruitment in rheumatic diseases

Szollosi

Manzoor

Aquilato

et al. 2017

Journal of Pharmacy and Pharmacology

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Objectives Many studies of disease state mechanisms reveal that unbridled inflammation is to blame for many of the symptoms associated with autoimmune diseases such as Crohn’s and Rheumatoid Arthritis (RA). While therapies aimed at decreasing levels of pro‐inflammatory cytokines exist, some have failed clinically or have extensive adverse effects. The aim of this review is to discuss common drug targets for anti‐inflammatory therapies as well as explore potential mechanisms of action for new therapies. Various studies done on novel mechanisms targeting pro‐inflammatory cytokine release as well as leukocyte chemotaxis have been researched for discussion here. Both of these contribute to tissue injury and patient symptoms in inflammatory and autoimmune disease states. Key findings While many current drug targets suppress inflammation via the receptor, research aimed at identifying new compounds and signaling mechanisms is ongoing to identify new targets within pro‐inflammatory signaling pathways, or specific immune cell types. Conclusions While glucocorticoids and monoclonal antibodies have shown to be efficacious, some patients have encountered mixed results. Biologic therapies also come with a high price tag Thus, novel compounds with new immune drug targets are ideal for patients whose therapies have not been successful.

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“…Piperazine-1-carboxamides have diverse actions such as antagonism of CB 1 , human CCR2 chemokine, androgen and vanilloid receptors or inhibition of PDGFR phosphorylation [1][2][3][4][5] . Benzhydrylpiperazine scaffold is well known for its antihistaminic activity [6][7][8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and cytotoxicity studies of novel benzhydrylpiperazine carboxamide and thioamide derivatives

Gurdal

Durmaz

Cetin-Atalay

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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Synthesis and cytotoxic activities of 32 benzhydrylpiperazine derivatives with carboxamide and thioamide moieties were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. In general, 4-chlorobenzhydrylpiperazine derivatives were more cytotoxic than other compounds. In addition, thioamide derivatives (6a-g) have higher growth inhibition than their carboxamide analogs.

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The design and synthesis of novel, potent and orally bioavailable N-aryl piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity

Cited by 17 publications

References 24 publications

Structural Analysis of Chemokine Receptor–Ligand Interactions

Structural Analysis of Chemokine Receptor–Ligand Interactions

Current and novel anti-inflammatory drug targets for inhibition of cytokines and leucocyte recruitment in rheumatic diseases

Synthesis and cytotoxicity studies of novel benzhydrylpiperazine carboxamide and thioamide derivatives

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