化学
兴奋剂
生物利用度
甲状旁腺激素
甲状旁腺机能减退
微粒体
内分泌学
磺酰
内科学
体外
溶解度
受体
药理学
钙
生物化学
医学
有机化学
烷基
作者
Yoshikazu Nishimura,Toru Esaki,Yoshiaki Isshiki,Naoki Okamoto,Yoshiaki Furuta,Tomoya Kotake,Yoshiaki Watanabe,Masateru Ohta,Tatsuo Nakagawa,Hiroshi Noda,Masaru Shimizu,Hitoshi Saitô,Tatsuya Tamura,Haruhiko Sato
标识
DOI:10.1021/acs.jmedchem.8b00182
摘要
During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1R,4R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC20 of 3.0 μM and EC50 of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.
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