发现一种用于治疗良性前列腺增生的慢紧密结合型LPA1拮抗剂（ONO-0300302）。
Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia.
作者信息
Terakado Masahiko, Suzuki Hidehiro, Hashimura Kazuya, Tanaka Motoyuki, Ueda Hideyuki, Hirai Keisuke, Asada Masaki, Ikura Masahiro, Matsunaga Naoki, Saga Hiroshi, Shinozaki Koji, Karakawa Naoko, Takada Yuka, Minami Masashi, Egashira Hiromu, Sugiura Yoshihiro, Yamada Masanori, Nakade Shinji, Takaoka Yoshikazu
机构信息
Medicinal Chemistry Research Laboratories, Exploratory Research Laboratories, and Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
出版信息
ACS Med Chem Lett. 2017 Nov 20;8(12):1281-1286. doi: 10.1021/acsmedchemlett.7b00383. eCollection 2017 Dec 14.
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 .
从先导化合物（）的酰胺基团进行骨架跃迁到仲醇，成功得到了一种新型化学类型的溶血磷脂酸受体1（LPA）拮抗剂（）。使用大鼠离体尿道进行的洗脱实验表明，化合物（）对LPA受体具有紧密结合特性。将（）的两个苯基进一步修饰为吡咯和茚满部分，得到了优化化合物（）。尽管化合物（）的清除率较高，但在大鼠（3 mg/kg，）和犬（1 mg/kg，）体内，它在12小时内显著抑制了LPA诱导的尿道内压（IUP）升高。与化合物（）的结合实验表明，观察到的长效作用是由于化合物（）的缓慢紧密结合特性。
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