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

Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA. A high throughput screen against LPA gave compound as a hit. The subsequent optimization of led to () as a novel, potent LPA antagonist, which showed good efficacy . The oral dosing of at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound had no impact on the mean blood pressure at this dose. These results suggest that LPA 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 LPA antagonists and their efficacy.