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 [³H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.

中文翻译：

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缓慢紧密结合的LPA1拮抗剂（ONO-0300302）的发现，用于治疗良性前列腺增生

从铅化合物ONO-7300243（1）的酰胺基跃迁到仲醇上的支架成功产生了一种新的化学型溶血磷脂酸受体1（LPA ₁）拮抗剂4。使用大鼠离体尿道的冲洗实验表明，化合物4具有与LPA ₁受体的紧密结合特征。将1的两个苯基进一步修饰为吡咯和茚满部分，得到优化的化合物ONO-0300302（19）。尽管IV清除率很高，但19抑制LPA诱导的大鼠（3 mg / kg，口服）和狗（1 mg / kg，口服）在12小时内尿道内压力（IUP）升高。[ ³ H] -ONO-0300302的结合实验表明，观察到的长效作用是由于19的缓慢紧密结合特性。