溶血磷脂酸
部分
敌手
化学
酰胺
受体
立体化学
生物物理学
生物化学
生物
作者
Masahiko Terakado,Hidehiro Suzuki,Kazuya Hashimura,Motoyuki Tanaka,Hideyuki Ueda,Keisuke Hirai,Masaki Asada,Masahiro Ikura,Naoki Matsunaga,Hiroshi Saga,Koji Shinozaki,Naoko Karakawa,Yuka Takada,Michiko Minami,Hiromu Egashira,Yoshimi Sugiura,Masanori Yamada,Shinji Nakade,Yousuke Takaoka
标识
DOI:10.1021/acsmedchemlett.7b00383
摘要
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 (LPA 1 ) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA 1 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.
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