Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia.

Scaffold hopping from the amide group of lead compound () to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA) antagonist . Wash-out experiments using rat isolated urethra showed that compound possesses a tight binding feature to the LPA receptor. Further modification of two phenyl groups of to pyrrole and an indane moiety afforded an optimized compound ().

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 .

Discovery of novel S1P2 antagonists. Part 2: Improving the profile of a series of 1,3-bis(aryloxy)benzene derivatives.

Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1, which was previously reported by our group to be an S1P2 antagonist.