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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 LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the ?1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1 antagonists and their in vivo efficacy.

SUBMITTER: Terakado M 

PROVIDER: S-EPMC5066152 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead.

Terakado Masahiko M   Suzuki Hidehiro H   Hashimura Kazuya K   Tanaka Motoyuki M   Ueda Hideyuki H   Kohno Hiroshi H   Fujimoto Taku T   Saga Hiroshi H   Nakade Shinji S   Habashita Hiromu H   Takaoka Yoshikazu Y   Seko Takuya T  

ACS medicinal chemistry letters 20160819 10

Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA<sub>1-6</sub>. A high throughput screen against LPA<sub>1</sub> gave compound <b>7a</b> as a hit. The subsequent optimization of <b>7a</b> led to <b>ONO-7300243</b> (<b>17a</b>) as a novel, potent LPA<sub>1</sub> antagonist, which showed good efficacy <i>in vivo</i>. The oral dosing of <b>17a</b> at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this c  ...[more]

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