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

  • ACS Med Chem Lett. 2017 Nov 20;8(12):1281-1286. doi: 10.1021/acsmedchemlett.7b00383.
Masahiko Terakado  1 ,  Hidehiro Suzuki  1 ,  Kazuya Hashimura  1 ,  Motoyuki Tanaka  1 ,  Hideyuki Ueda  1 ,  Keisuke Hirai  1 ,  Masaki Asada  1 ,  Masahiro Ikura  1 ,  Naoki Matsunaga  1 ,  Hiroshi Saga  1 ,  Koji Shinozaki  1 ,  Naoko Karakawa  1 ,  Yuka Takada  1 ,  Masashi Minami  1 ,  Hiromu Egashira  1 ,  Yoshihiro Sugiura  1 ,  Masanori Yamada  1 ,  Shinji Nakade  1 ,  Yoshikazu Takaoka  1
Affiliations
  • 1. 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.
PMID: 29259748 DOI: 10.1021/acsmedchemlett.7b00383
Abstract

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.

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