RS-1748, a novel CC chemokine receptor 4 antagonist, inhibits ovalbumin-induced airway inflammation in guinea pigs.

Abstract

CC chemokine receptor 4 (CCR4) is generally recognized as a preferential marker for T helper 2 cells, and we have previously reported morpholine-derivative CCR4 antagonists, RS-1154 and RS-1269. Here, we investigate the pharmacological profiles of a novel pyrimidine-derivative CCR4 antagonist, 2-{4-[2-(diethylamino)ethoxy]phenyl}-N-(2,4-difluorobenzyl)-5-fluoropyrimidin-4-amine (RS-1748), which showed potency to inhibit the bindings of [(125)I]CCL17 and [(35)S]GTPgammaS to human CCR4-expressing Chinese hamster ovary (CHO) cells with IC(50) values of 59.9 nM and 18.4 nM, respectively. Furthermore, RS-1748 inhibited ovalbumin-induced airway inflammation in guinea pigs at a dose of 10 mg/kg. These results indicate that RS-1748 would be a promising lead compound for developing a therapeutic agent against asthma.

• Authors: Yasuhiro Nakagami, Yumi Kawase, Kazuki Yonekubo, Emi Nosaka, Maki Etori, Sakiko Takahashi, Nana Takagi, Takeshi Fukuda, Takeshi Kuribayashi, Futoshi Nara, Makoto Yamashita
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 33 Issue 6 Pg. 1067-9 ( 2010) ISSN: 1347-5215 [Electronic] Japan
• PMID: 20522980 (Publication Type: Journal Article)

Chemical References

• 2-(4-(2-(diethylamino)ethoxy)phenyl)-N-(2,4-difluorobenzyl)-5-fluoropyrimidin-4-amine
• Anti-Inflammatory Agents
• Chemokine CCL17
• Pyrimidines
• Receptors, CCR4
• Guanosine 5'-O-(3-Thiotriphosphate)
• Ovalbumin

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Asthma (drug therapy)
• Bronchial Hyperreactivity (chemically induced, drug therapy, metabolism)
• CHO Cells
• Chemokine CCL17 (metabolism)
• Cricetinae
• Cricetulus
• Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
• Guinea Pigs
• Humans
• Inflammation (chemically induced, drug therapy, metabolism)
• Inhibitory Concentration 50
• Male
• Ovalbumin
• Pyrimidines (pharmacology, therapeutic use)
• Receptors, CCR4 (antagonists & inhibitors)