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.

中文翻译：

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新型人类甲状旁腺激素受体1（hPTHR1）激动剂（CH5447240）的开发，这是一种有效的口服小分子药物，可治疗甲状旁腺功能减退症

在HTS hit 4a衍生化的过程中，我们已经确定了一种新型的小分子hPTHR1激动剂1-（3,5-二甲基-4-（2-（（2-（（（（1 R，4 R）-4-甲基环己基）-4-氧代-1,3,8-三氮杂螺[4.5]癸-1-烯-8-基）磺酰基）乙基）苯基）-1-甲基脲（CH5447240，14升）。化合物14l表现出有效的体外hPTHR1激动剂作用，EC ₂₀为3.0μM ，EC ₅₀为12μM，并表现出优异的理化性质，例如在禁食状态下模拟肠液中的高溶解度以及在人肝微粒体内的良好代谢稳定性。重要的是14公升 在低血钙模型大鼠中显示出55％的口服生物利用度和显着升高的血清钙水平。