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 (). Despite its high clearance, inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, ) and dog (1 mg/kg, ) over 12 h. Binding experiments with suggest that the observed long duration action is because of the slow tight binding character of .