title: Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead.
abstract: Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1gave compound7aas a hit. The subsequent optimization of7aled toONO-7300243(17a) as a novel, potent LPA1antagonist, which showed good efficacyin vivo. The oral dosing of17aat 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound17ahad no impact on the mean blood pressure at this dose. These results suggest that LPA1antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1antagonists and theirin vivoefficacy.
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Masahiko
authors: M
authors: Terakado
authors: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd. , 17-2 Wadai, Tsukuba, Ibaraki 300-4247, Japan.
authors: Hidehiro
authors: H
authors: Suzuki
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Kazuya
authors: K
authors: Hashimura
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Motoyuki
authors: M
authors: Tanaka
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Hideyuki
authors: H
authors: Ueda
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Hiroshi
authors: H
authors: Kohno
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Taku
authors: T
authors: Fujimoto
authors: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd. , 17-2 Wadai, Tsukuba, Ibaraki 300-4247, Japan.
authors: Hiroshi
authors: H
authors: Saga
authors: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd. , 17-2 Wadai, Tsukuba, Ibaraki 300-4247, Japan.
authors: Shinji
authors: S
authors: Nakade
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Hiromu
authors: H
authors: Habashita
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Yoshikazu
authors: Y
authors: Takaoka
authors: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors: Takuya
authors: T
authors: Seko
keywords: GPCR; LPA1 antagonist; SAR; benign prostatic hyperplasia; hit-to-lead optimization