jm050085k_si_001.pdf (30.52 kB)
Discovery of Diphenyloxazole and Nδ-Z-Ornithine Derivatives as Highly Potent and Selective Human Prostaglandin EP4 Receptor Antagonists
journal contributionposted on 2005-05-05, 00:00 authored by Kouji Hattori, Akira Tanaka, Naoaki Fujii, Hisashi Takasugi, Yoshiyuki Tenda, Masayuki Tomita, Shoko Nakazato, Keiko Nakano, Yasuko Kato, Yutaka Kono, Hidetsugu Murai, Kazuo Sakane
Two novel classes of diphenyloxazole and Nδ-Z-ornithine derivatives as highly potent and selective EP4 antagonists have been discovered. The optimized diphenyloxzole 8 and Nδ-Z-ornithine 11 effectively competed with [3H]PGE2 binding to human recombinant EP4, with Ki values of 0.30 nM and 0.91 nM, respectively, and were selective for all members of the human prostanoid receptor family. 8 was shown to exhibit good pharmacokinetic properties in rats and dogs and potent inhibitory activity toward in vitro PGE2-promoted IgE synthesis.