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 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.