Potent and orally bioavailable CCR4 antagonists: Synthesis and structure-activity relationship study of 2-aminoquinazolines

  • Bioorg Med Chem. 2009 Jan 1;17(1):64-73. doi: 10.1016/j.bmc.2008.11.020.
Kazuhiro Yokoyama  1 ,  Noriko Ishikawa ,  Susumu Igarashi ,  Noriyuki Kawano ,  Naoyuki Masuda ,  Wataru Hamaguchi ,  Shingo Yamasaki ,  Yohei Koganemaru ,  Kazuyuki Hattori ,  Takahiro Miyazaki ,  Shin-Ichi Ogino ,  Yuzo Matsumoto ,  Makoto Takeuchi ,  Mitsuaki Ohta
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. [email protected]
PMID: 19081254 DOI: 10.1016/j.bmc.2008.11.020
Abstract

Starting with a series of CC chemokine receptor-4 (CCR4) antagonists developed in a previous study, the potency was improved by replacing the pyrrolidine moiety of N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 2 with a 3-(hydroxymethyl)piperidine. The resulting compound (1'-{4-[(4-chlorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}-1,4'-bipiperidin-3-yl)methanol 8ic was a strong inhibitor of human/mouse chemotaxis. Oral administration of 8ic showed anti-inflammatory activity in a murine model of acute dermatitis (oxazolone-induced contact hypersensitivity test) in a dose-dependent manner.

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