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 ONO-7300243 ( 1 ) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1 ) antagonist 4 . Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 ( 19 ). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o. ) and dog (1 mg/kg, p.o. ) over 12 h. Binding experiments with [ 3 H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19 .