Discovery and characterization of potent and efficacious small-molecule parathyroid hormone Receptor-1 (PTH1R) antagonists for the treatment of hypercalcemia.

Primary hyperparathyroidism (PHPT) is caused by the enlargement and overactivation of one or more of the parathyroid glands, via parathyroid adenomas or hyperplasia. This results in over-secretion of PTH hormone, which results in agonism of PTH1R and subsequent hypercalcemia. Blocking PTH action via an oral, small-molecule PTH1R antagonist may provide a convenient and improved therapy for PHPT. Herein, we report the discovery, optimization and characterization of a highly potent, bioavailable and efficacious series represented by 9c (hPTH1R IC50 = 5.2 nM), which based on pharmacokinetics and biological activity, represents a significant preclinical advancement in the development of small-molecule PTH antagonists.