Pyrrolinone derivatives as a new class of P2X3 receptor antagonists Part 2: Discovery of orally bioavailable compounds期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

Pyrrolinone derivatives as a new class of P2X3 receptor antagonists Part 2: Discovery of orally bioavailable compounds

Authors:	Hiroyuki Tobinaga Takayuki Kameyama Kentarou Asahi Tohru Horiguchi Miho Oohara Yukio Tada Kouki Fuchino Sae Jikihara Takeshi Endoh Naoko Kurihara Yasuhiko Kanda Masayoshi Ogawa Naomi Tamura Shigenori Yagi Emiko Taniguchi Yukio Takahara Shinji Shimada Chie Takeyama Hiroyuki Kai

Affiliation:	1. Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan;2. Office for Children’s Bright Future, Shionogi & Co., Ltd., 2F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan;3. Digital Intelligence Department, Shionogi & Co., Ltd., 2F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan;4. Research Management & Planning Office, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan;5. Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan;6. Research Laboratory for Development, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan;7. API R&D Center, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan;8. Shionogi Techno Advance Research Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan;9. Shionogi Marketing Solutions Co., Ltd., 8F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan

Abstract:	Some P2X3 receptor antagonists have been developed as new therapeutic drugs for pain. We discovered a novel chemotype of P2X3 receptor antagonists with a pyrrolinone skeleton. Because of SAR studies to improve bioavailability of lead compound 2, compound (R)-24 was identified, which showed an analgesic effect against neuropathic pain by oral administration. We constructed a human P2X3 homology model as a template for the zebrafish P2X4 receptor, which agreed with SAR studies of pyrrolinone derivatives.

Keywords:	Purinergic receptors Ion channels P2X3 receptor antagonists Pyrrolinone derivatives Pain
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