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

• Published in: ACS medicinal chemistry letters 2017-12, Vol.8 (12), p.1281-1286
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.7b00383

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.