Sequence: RecName: Full=C-C chemokine receptor type 7; Short=C-C CKR-7; Short=CC-CKR-7; Short=CCR-7; AltName: Full=BLR2; AltName: Full=CDw197; AltName: Full=Epstein-Barr virus-induced G-protein coupled receptor 1; Short=EBI1; Short=EBV-induced G-protein coupled receptor 1; AltName: Full=MIP-3 beta receptor; AltName: CD_antigen=CD197; Flags: Precursor
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Gene:CCR7     Conserved Domain     Related Protein 3D Structures

Title: Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent Anti-HIV-1 activity.

Abstract: We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC(50) = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl)piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC(50) = 3.5 nM) and potent inhibition of membrane fusion (IC(50) = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC(50) = 1.1 nM, EC(90) = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.
(PMID: 16640339)

ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Target ID: 100434

ChEMBL target type: Target is a single protein chain