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

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; Shoichi Yamamoto; Shunji Shinohara; Hiroyuki Kai

doi:10.1016/j.bmcl.2019.01.039

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

Bioorg Med Chem Lett. 2019 Mar 1;29(5):688-693. doi: 10.1016/j.bmcl.2019.01.039. Epub 2019 Feb 1.

Authors

Hiroyuki Tobinaga¹, Takayuki Kameyama², Kentarou Asahi³, Tohru Horiguchi³, Miho Oohara³, Yukio Tada³, Kouki Fuchino³, Sae Jikihara⁴, Takeshi Endoh⁵, Naoko Kurihara⁶, Yasuhiko Kanda³, Masayoshi Ogawa³, Naomi Tamura⁷, Shigenori Yagi⁸, Emiko Taniguchi⁶, Yukio Takahara⁶, Shinji Shimada⁹, Chie Takeyama⁹, Shoichi Yamamoto¹⁰, Shunji Shinohara⁹, Hiroyuki Kai¹¹

Affiliations

¹ Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: [email protected].
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 Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
⁴ Digital Intelligence Department, Shionogi & Co., Ltd., 2F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan.
⁵ Research Management & Planning Office, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
⁶ Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
⁷ Research Laboratory for Development, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
⁸ API R&D Center, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan.
⁹ Shionogi Techno Advance Research Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
¹⁰ Shionogi Marketing Solutions Co., Ltd., 8F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan.
¹¹ Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: [email protected].

PMID: 30728111
DOI: 10.1016/j.bmcl.2019.01.039

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: Ion channels; P2X3 receptor antagonists; Pain; Purinergic receptors; Pyrrolinone derivatives.

MeSH terms

Administration, Oral
Biological Availability
Drug Discovery
High-Throughput Screening Assays
Humans
Inhibitory Concentration 50
Neuralgia / drug therapy
Purinergic P2X Receptor Antagonists / administration & dosage
Purinergic P2X Receptor Antagonists / pharmacokinetics
Purinergic P2X Receptor Antagonists / pharmacology*
Purinergic P2X Receptor Antagonists / therapeutic use
Pyrroles / pharmacology*
Receptors, Purinergic P2X3 / drug effects*
Structure-Activity Relationship

Substances

Purinergic P2X Receptor Antagonists
Pyrroles
Receptors, Purinergic P2X3