A novel, selective, and orally available antagonist for CC chemokine receptor 3.
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(+) T helper 2 cells) in allergic inflammation incidents, including asthma and rhinitis. A newly synthesized compound, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-{1-[(5-hydroxy-3-methylpyridin-2-yl)carbonyl]piperidin-4-ylidene}-acetamide hemifumarate (YM-355179), inhibited the binding of CCL11 and CCL5/regulated on activation normal T cell expressed and secreted to CCR3-expressing B300-19 cells with IC(50) values of 7.6 and 24 nM, respectively. In contrast, YM-355179 did not affect the binding of CCL5 to CCR1 or CCR5. In functional assays, YM-355179 inhibited CCL11-induced, intracellular Ca(2+) influx, chemotaxis, and eosinophil degranulation with IC(50) values of 8.0, 24, and 29 nM, respectively. YM-355179 did not, however, affect any CC chemokine receptor (CCR1, CCR2, CCR4, or CCR5)-mediated Ca(2+) influx signals. Furthermore, oral administration of YM-355179 (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.
Morokata
Tatsuaki
T
Inflammation Research Pharmacology Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan. tatsuaki.morokata@jp.astellas.com
Suzuki
Keiko
K
Masunaga
Yohei
Y
Taguchi
Katsunari
K
Morihira
Koichiro
K
Sato
Ippei
I
Fujii
Masahiro
M
Takizawa
Satoko
S
Torii
Yuichi
Y
Yamamoto
Naoyoshi
N
Kaneko
Masayuki
M
Yamada
Toshimitsu
T
Takahashi
Koichiro
K
Shimizu
Yasuaki
Y
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects*; D045744:Cell Line, Tumor; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003001:Cloning, Molecular; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008024:Ligands; D008168:Lung / Q000187:drug effects; D008252:Macaca fascicularis; D051379:Mice; D015394:Molecular Structure; D009019:Morphinans / Q000008:administration & dosage / Q000494:pharmacology*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
C510434:2-((4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino)acetic acid; C515456:CCL11 protein, human; C515350:CCR3 protein, human; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D004852:Epoxy Compounds; D008024:Ligands; D009019:Morphinans; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D002118:Calcium