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

Basic Information

ID: ALA4138255

Journal: ACS Med Chem Lett

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

Authors: Terakado M, Suzuki H, Hashimura K, Tanaka M, Ueda H, Hirai K, Asada M, Ikura M, Matsunaga N, Saga H, Shinozaki K, Karakawa N, Takada Y, Minami M, Egashira H, Sugiura Y, Yamada M, Nakade S, Takaoka Y.

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.

CiteXplore: 29259748

DOI: 10.1021/acsmedchemlett.7b00383

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