Discovery of CC Chemokine Receptor-3 (CCR3) Antagonists with Picomolar Potency

Lucca, George V. De; Kim, Ui Tae; Vargo, Brian J.; Duncia, John V.; Santella, Joseph B.; Gardner, Daniel S.; Zheng, Changsheng; Liauw, Ann Y.; Wang, Zhang; Emmett, George; Wacker, Dean A.; Welch, Patricia; Covington, Maryanne; Stowell, Nicole; Wadman, Eric; Das, Anuk; Davies, Paul; Yeleswaram, Swamy; Graden, Danielle; Solomon, Kimberly A.; Newton, Robert; Trainor, George L.; Decicco, Carl P.; Ko, Soo S.

doi:10.1021/jm049530m

Cited by 63 publications

(44 citation statements)

References 44 publications

(59 reference statements)

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“…However, these phenethyl-linked compounds showed significant affinity for other GPCRs. 56 For example, 24e was reported to bind 5HT 2A receptors with a K i value of 11 nM. Although the selectivity for CCR3 over 5HT 2A was improved in case of the benzyl-linked analogues (n 5 1, not shown), the potency was reduced simultaneously.…”

Section: E (N-ureidoalkyl)benzylpiperidines and N-arylalkylpiperidinmentioning

confidence: 95%

Small molecule antagonists for chemokine CCR3 receptors

Willems

IJzerman

2010

Medicinal Research Reviews

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The chemokine receptor CCR3 is believed to play a role in the development of allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis. Despite the conflicting results that have been reported regarding the importance of eosinophils and CCR3 in allergic inflammation, inhibition of this receptor with small molecule antagonists is thought to provide a valuable approach for the treatment of these diseases. This review describes the structure-activity relationships (SAR) of small molecule CCR3 antagonists as reported in the scientific and patent literature. Various chemical classes of small molecule CCR3 antagonists have been described so far, including (bi)piperidine and piperazine derivatives, N-arylalkylpiperidine urea derivatives and (N-ureidoalkyl)benzylpiperidines, phenylalanine derivatives, morpholinyl derivatives, pyrrolidinohydroquinazolines, arylsulfonamides, amino-alkyl amides, imidazole- and pyrimidine-based antagonists, and bicyclic diamines. The (N-ureidoalkyl)benzylpiperidines are the best studied class in view of their generally high affinity and antagonizing potential. For many of these antagonists subnanomolar IC(50) values were reported for binding to CCR3 along with the ability to effectively inhibit intracellular calcium mobilization and eosinophil chemotaxis induced by CCR3 agonist ligands in vitro.

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Section: E (N-ureidoalkyl)benzylpiperidines and N-arylalkylpiperidinmentioning

confidence: 95%

Small molecule antagonists for chemokine CCR3 receptors

Willems

IJzerman

2010

Medicinal Research Reviews

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“…This has been typical of some chemical series of our CCR3-active molecules (Delucca et al, 2005) but has not been reflected in their potencies against mouse CCR3. Compound 2 was unusual in exhibiting subnanomolar chemotaxis IC 50 against mouse CCR3, a 15-fold increase in potency over the binding number.…”

Section: Discussionmentioning

confidence: 90%

“…However, chemotaxis IC 50 were divergent. Like other compounds in the cyclohexyl series (Delucca et al, 2005), compound 1 was somewhat less potent in the chemotaxis assay than in binding; in contrast, compound 2 was 15-fold more potent in mouse chemotaxis, just as it was more potent in human chemotaxis than in human binding. When dosed p.o.…”

Section: Development and Characterization Of A Model Of Ccr3-dependenmentioning

confidence: 85%

“…4. These molecules are representative analogs of two distinct chemical series developed in our laboratories: compound 1 is a heterocyclic derivative of the cyclohexyl-linked series of inhibitors (Ko et al, 2002;Delucca et al, 2005), and compound 2 is a propyl-linked derivative that contains an alternate piperidine headgroup (Watson et al, 2002;Varnes et al, 2004). Both compounds were found to be potent antagonists of human CCR3 binding and function (Table 2).…”

Section: Development and Characterization Of A Model Of Ccr3-dependenmentioning

confidence: 99%

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Selective Inhibition of Eosinophil Influx into the Lung by Small Molecule CC Chemokine Receptor 3 Antagonists in Mouse Models of Allergic Inflammation

Das

Vaddi²,

Solomon³

et al. 2006

J Pharmacol Exp Ther

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CC chemokine receptor (CCR) 3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils (E⌽), to the lung in episodes of allergic asthma. To investigate the efficacy of selective, small molecule antagonists of CCR3, we developed a murine model of E⌽ recruitment to the lung. Murine eotaxin was delivered intranasally to mice that had previously received i.p. injections of ovalbumin (OVA), and the effects were monitored by bronchoalveolar lavage. A selective eosinophilic influx was produced in animals receiving eotaxin but not saline. Furthermore, the number of E⌽ was concentration-and timedependent. Although anti-CCR3 antibody reduced the number of E⌽, the effect of eotaxin in OVA-sensitized mice was not a direct chemotactic stimulus because mast cell deficiency (in WBB6F 1 -Kit w /Kit w-v mice) significantly reduced the response. Two representative small molecule CCR3 antagonists from our program were characterized as being active at mouse CCR3. They were administered p.o. to wild-type mice and found to reduce eotaxin-elicited E⌽ selectively in a dose-dependent manner. Pump infusion of one of the inhibitors to achieve steady-state levels showed that efficacy was not achieved at plasma concentrations equivalent to the in vitro chemotaxis IC 90 but only at much higher concentrations. To extend the results from our recruitment model, we tested one of the inhibitors in an allergenic model of airway inflammation, generated by adoptive transfer of OVA-sensitive murine T helper 2 cells and aerosolized OVA challenge of recipient mice, and found that it inhibited E⌽ recruitment. We conclude that small molecule CCR3 antagonists reduce pulmonary eosinophilic inflammation elicited by chemokine or allergenic challenge.

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“…Although several nonpeptide compounds that inhibit binding of CCL11 to CCR3 have been reported (Sabroe et al, 2000;White et al, 2000;Saeki et al, 2001;Wan et al, 2002, De Lucca et al, 2005, their in vivo effectiveness has not yet been demonstrated in any nonhuman primates. YM-355179 is a novel, selective, and orally available low-molecular weight CCR3 antagonist that has been chemically synthesized in our laboratories.…”

mentioning

confidence: 99%

A Novel, Selective, and Orally Available Antagonist for CC Chemokine Receptor 3

Morokata¹,

Suzuki²,

Masunaga³

et al. 2005

J Pharmacol Exp Ther

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CC chemokine ligand 11 (CCL11/eotaxin) and other CC chemokine receptor 3 (CCR3) ligands (CCL24/eotaxin-2, CCL26/ eotaxin-3, CCL13/monocyte chemotactic protein-4, etc.) play important roles in the chemotaxis and activation of eosinophils and other CCR3-expressing cells (basophils, mast cells, and CD4 ϩ T helper 2 cells) in allergic inflammation incidents, including asthma and rhinitis. A newly synthesized compound, (1 mg/kg) inhibited CCL11-induced shape change of whole blood eosinophils in cynomolgus monkeys. Intravenous injection of YM-355179 (1 mg/kg) also inhibited eosinophil infiltration into airways of cynomolgus monkeys after segmental bronchoprovocation with CCL11. These results indicate that YM-355179 is a novel, selective, and orally available CCR3 antagonist with therapeutic potential for treating eosinophil-related allergic inflammatory diseases.Eosinophils play a crucial role in allergic diseases such as bronchial asthma and allergic rhinitis (Durham and Kay, 1985;Terada et al., 1994). CCR3, a seven-transmembranespanning G protein-coupled receptor, is a major chemokine receptor expressed on allergic inflammatory cells including not only eosinophils but also basophils, mast cells, and T helper 2-type CD4 ϩ cells (Combadiere et al., 1995;Post et al., 1995;Sabroe et al., 1998). This receptor has been identified in humans, monkeys, mice, rats, and guinea pigs (GarciaZepeda et al., 1996;Forssmann et al., 1997;Sallusto et al., 1997;Zhang et al., 2002). Human CCR3 binds multiple chemokine ligands such as CCL11/eotaxin, CCL24/eotaxin-2, CCL26/eotaxin-3, and CCL13/MCP-4 with high affinity, whereas CCR3 binds CCL5/regulated on activation normal T cell expressed and secreted and CCL7/MCP-3 with lower affinity (Forssmann et al., 1997;Stellato et al., 1997;Doucet et al., 1998). CCR3 ligands are produced by multiple cell types, including lung and mucosal fibroblast cells, bronchial epithelial cells, vascular endothelial cells, smooth muscle cells, macrophages, mast cells, and eosinophils (Lamkhioued et al., 1997;Lilly et al., 1997;Shinkai et al., 1999;Hirst et al., 2002;Menzies-Gow et al., 2004). The binding of CCR3 ligands to CCR3 on the surface of eosinophils causes a transient increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) that activates several signal pathways, including actin polymerization (Elsner et al., 1996). With activation of the intracellular motile apparatus, eosinophils undergo shape change

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Discovery of CC Chemokine Receptor-3 (CCR3) Antagonists with Picomolar Potency

Cited by 63 publications

References 44 publications

Small molecule antagonists for chemokine CCR3 receptors

Small molecule antagonists for chemokine CCR3 receptors

Selective Inhibition of Eosinophil Influx into the Lung by Small Molecule CC Chemokine Receptor 3 Antagonists in Mouse Models of Allergic Inflammation

A Novel, Selective, and Orally Available Antagonist for CC Chemokine Receptor 3

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