Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism
Parathyroid hormone (PTH) plays a crucial role in regulating calcium levels in the body, primarily through its interaction with the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. While PTH injections are used to treat conditions such as hypoparathyroidism and osteoporosis, there is no orally available PTH analogue. In this study, we introduce PCO371, a novel small molecule that functions as a full agonist of PTHR1 and is effective when taken orally. Notably, PCO371 does not interact with the PTH type 2 receptor (PTHR2), and experiments with PTHR1-PTHR2 chimeric receptors identified Proline 415 of PTHR1 as essential for PCO371-induced activation. In osteopenic rats, oral PCO371 administration significantly increased bone turnover, though with a modest rise in bone mass. In hypocalcemic rats, PCO371 effectively restored serum calcium levels without raising urinary calcium, exhibiting stronger and more sustained effects compared to PTH injections. These findings suggest that PCO371 could offer a promising new therapeutic option for PTH-related disorders, such as hypoparathyroidism.