2. Academic Validation
  3. Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia

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

Affiliation

  • 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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