Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHRl agonist, l-(3,5-dimethyl-4-(2-((2-((lR,4R)-4-methylcyclohexyl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)sulfonyl)ethyl)-phenyl)-l-methylurea (CH5447240, 141). Compound 141 exhibited a potent in vitro hPTHRl agonist effect with EC20 of 3.0 mu M and EC50 of 12 mu M and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 141 showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.