Abstract
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.