Design, Synthesis, and Discovery of a Novel CCR1 Antagonist

Naya, Akira; Sagara, Yufu; Ohwaki, Kenji; Saeki, Toshihiko; Ichikawa, Daisuke; Iwasawa, Yoshikazu; Noguchi, Kazuhito; Ohtake, Norikazu

doi:10.1021/jm0004244

Cited by 92 publications

(42 citation statements)

References 15 publications

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“…Most notably, the basic nitrogen of the compounds is postulated to interact with a common acidic amino acid in TM7 of the receptor. Indeed, the quaternization of forerunners of the compound we describe here has been reported to increase their binding to the receptor (38). Although three of the analogous residues appear to interact with UCB 35625, we were unable to demonstrate a significant effect of the T86A mutation despite an apparent reduction in sensitivity to the compound.…”

Section: Mapping the Site Of Interaction For Ccr1-ucb 35625-contrasting

confidence: 59%

Site-directed Mutagenesis of CC Chemokine Receptor 1 Reveals the Mechanism of Action of UCB 35625, a Small Molecule Chemokine Receptor Antagonist

Mendonça

Fonseca

Phillips

et al. 2005

Journal of Biological Chemistry

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The chemokine receptor CCR1 and its principal ligand, CCL3/MIP-1␣, have been implicated in the pathology of several inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and asthma. As such, these molecules are the focus of much research with the ultimate aim of developing novel therapies. We have described previously a non-competitive small molecule antagonist of CCR1 (UCB 35625), which we hypothesized interacted with amino acids located within the receptor transmembrane (TM) helices (Sabroe, I., Peck, M. J., Jan Van Keulen, B., Jorritsma, A., Simmons, G., Clapham, P. R., Williams, T. J., and Pease, J. E. (2000) J. Biol. Chem. 275, 25985-25992). Here we describe an approach to identifying the mechanism by which the molecule antagonizes CCR1. Thirty-three point mutants of CCR1 were expressed transiently in L1.2 cells, and the cells were assessed for their capacity to migrate in response to CCL3 in the presence or absence of UCB 35625. Cells expressing the mutant constructs Y41A (TM helix 1, or TM1), Y113A (TM3), and E287A (TM7) were responsive to CCL3 but resistant to the antagonist, consistent with a role for the TM helices in CCR1 interactions with UCB 35625. Subsequent molecular modeling successfully docked the compound with CCR1 and suggests that the antagonist ligates TM1, 2, and 7 of CCR1 and severely impedes access to TM2 and TM3, a region thought to be perturbed by the chemokine amino terminus during the process of receptor activation. Insights into the mechanism of action of these compounds may facilitate the development of more potent antagonists that show promise as future therapeutic agents in the treatment of inflammatory disease.

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Section: Mapping the Site Of Interaction For Ccr1-ucb 35625-contrasting

confidence: 59%

Site-directed Mutagenesis of CC Chemokine Receptor 1 Reveals the Mechanism of Action of UCB 35625, a Small Molecule Chemokine Receptor Antagonist

Mendonça

Fonseca

Phillips

et al. 2005

Journal of Biological Chemistry

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“…The increased potency of BX 521 and BX 523 relative to BX 513 and BX 522 shows that both human and mouse CCR1 benefit from the increased basicity of a quaternary ammonium salt on the piperidine. This result is similar to that reported for the Banyu xanthenecarboxamide series following replacement of the piperidine nitrogen with a quaternary ammonium group (11).…”

Section: Figuresupporting

confidence: 89%

“…These findings provided the first clear evidence of the impact of mouse/human species variability of CCR1 on nonpeptide receptor antagonist potency. Recently, researchers from Banyu have reported that CCR1 inhibitors based upon a xanthenecarboxamide template also exhibit differential potencies on human and mouse CCR1s (11). These results demonstrate that the CCR1 mouse/human species variability also effects compounds from different template classes, a finding that may result from these inhibitors using a common antagonist binding site on CCR1.…”

mentioning

confidence: 92%

Structure Function Differences in Nonpeptide CCR1 Antagonists for Human and Mouse CCR1

Onuffer¹,

McCarrick²,

Dunning³

et al. 2003

The Journal of Immunology

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A useful strategy for identifying ligand binding domains of G protein-coupled receptors has been the exploitation of species differences in antagonist potencies. We have used this approach for the CCR1 chemokine receptor with a novel series of antagonists, the 4-hydroxypiperidines, which were discovered by high throughput screening of human CCR1 and subsequently optimized. The structure-activity relationships for a number of different 4-hydroxypiperidine antagonists for human and mouse CCR1 were examined by receptor binding and functional assays. These compounds exhibit major differences in their rank order of potency for the human and mouse chemokine receptor CCR1. For example, the initial lead template, BX 510, which was a highly potent functional antagonist for human CCR1 (Ki = 21 nM) was >400-fold less active on mouse CCR1 (Ki = 9150 nM). However, increasing the length of the linker between the piperidine and dibenzothiepine groups by one methylene group generated a compound, BX 511, which was equipotent for both human and mouse CCR1. These and other analogs of the lead template BX 510, which have major differences in potency for human and mouse CCR1, are described, and a model for their interaction with human CCR1 is presented.

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“…Control animals received vehicle alone. This compound has been reported to block both human and murine CCR1 (34). Two hours after the anti-CXCR2 or 30 min after the CCR1 antagonist administration, 1 ml of carrageenan (1%) was injected into the pouches, and 4 h later animals were sacrificed, exudates were collected, and samples were processed and analyzed as described.…”

Section: Effect Cxcr2 or Ccr1 Blockade On Chemokine Synthesis And Leumentioning

confidence: 99%

Resident Cell Chemokine Expression Serves as the Major Mechanism for Leukocyte Recruitment During Local Inflammation

García-Ramallo

Marques

Prats

et al. 2002

The Journal of Immunology

165

149

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The mechanistic relationships between initiating stimulus, cellular source and sequence of chemokine expression, and leukocyte recruitment during inflammation are not clear. To study these relationships in an acute inflammatory process, we challenged a murine air pouch with carrageenan. A time-dependent increase in TNF-␣, monocyte chemottractant protein-1 (MCP-1), macrophage-inflammatory protein-1␣ (MIP-1␣), RANTES, KC, and MIP-2 was found in the exudates preceding cell recruitment, but displaying different kinetic profiles. Air pouches generated for 2, 6, or 9 days before initiating inflammation demonstrated a proportional increase in the number of cells lining the cavities. Two hours after carrageenan stimulation, the synthesis of TNF-␣ and all chemokines but RANTES increased in proportion to the lining cellularity, although no differences in infiltrating leukocytes were found, suggesting that the early source of these mediators is resident cells. To assess the contribution of neutrophils to chemokine synthesis at later time points, we used neutropenic animals. Neutrophil depletion caused a decrease in TNF-␣ (51%), KC (37%), MIP-1␣ (30%), and RANTES (57%) levels and a 2-fold increase in monocytes 4 h after challenge. No effect on MIP-2 and MCP-1 levels was observed. The selective blockade of CXCR2 or CCR1 inhibited neutrophil recruitment by 74% and 54%, respectively, without a significant inhibition of monocytes. A differential effect on TNF-␣ and MCP-1 levels was observed after these treatments, indicating that the two receptors did not subserve a mere redundant chemotactic role. Overall, our results suggest that chemokines synthesized by resident cells play an important role in the evolution of the inflammatory response.

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Design, Synthesis, and Discovery of a Novel CCR1 Antagonist

Cited by 92 publications

References 15 publications

Site-directed Mutagenesis of CC Chemokine Receptor 1 Reveals the Mechanism of Action of UCB 35625, a Small Molecule Chemokine Receptor Antagonist

Site-directed Mutagenesis of CC Chemokine Receptor 1 Reveals the Mechanism of Action of UCB 35625, a Small Molecule Chemokine Receptor Antagonist

Structure Function Differences in Nonpeptide CCR1 Antagonists for Human and Mouse CCR1

Resident Cell Chemokine Expression Serves as the Major Mechanism for Leukocyte Recruitment During Local Inflammation

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