Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism

  • Nat Commun. 2016 Nov 18;7:13384. doi: 10.1038/ncomms13384.
Tatsuya Tamura  1 ,  Hiroshi Noda  1 ,  Eri Joyashiki  1 ,  Maiko Hoshino  1 ,  Tomoyuki Watanabe  1 ,  Masahiko Kinosaki  1 ,  Yoshikazu Nishimura  1 ,  Tohru Esaki  1 ,  Kotaro Ogawa  1 ,  Taiji Miyake  1 ,  Shinichi Arai  1 ,  Masaru Shimizu  1 ,  Hidetomo Kitamura  1 ,  Haruhiko Sato  1 ,  Yoshiki Kawabe  1
Affiliations
  • 1. Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
PMID: 27857062 DOI: 10.1038/ncomms13384
Abstract

Parathyroid hormone (PTH) is essential for calcium homeostasis and its action is mediated by the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. Hypoparathyroidism and osteoporosis can be treated with PTH injections; however, no orally effective PTH analogue is available. Here we show that PCO371 is a novel, orally active small molecule that acts as a full agonist of PTHR1. PCO371 does not affect the PTH type 2 receptor (PTHR2), and analysis using PTHR1-PTHR2 chimeric receptors indicated that Proline 415 of PTHR1 is critical for PCO371-mediated PTHR1 activation. Oral administration of PCO371 to osteopenic rats provokes a significant increase in bone turnover with limited increase in bone mass. In hypocalcemic rats, PCO371 restores serum calcium levels without increasing urinary calcium, and with stronger and longer-lasting effects than PTH injections. These results strongly suggest that PCO371 can provide a new treatment option for PTH-related disorders, including hypoparathyroidism.

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