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

Author

Listed:
  • Tatsuya Tamura

    (Research Division)

  • Hiroshi Noda

    (Research Division)

  • Eri Joyashiki

    (Research Division)

  • Maiko Hoshino

    (Research Division)

  • Tomoyuki Watanabe

    (Research Division)

  • Masahiko Kinosaki

    (Research Division)

  • Yoshikazu Nishimura

    (Research Division)

  • Tohru Esaki

    (Research Division)

  • Kotaro Ogawa

    (Research Division)

  • Taiji Miyake

    (Research Division)

  • Shinichi Arai

    (Research Division)

  • Masaru Shimizu

    (Research Division)

  • Hidetomo Kitamura

    (Research Division)

  • Haruhiko Sato

    (Research Division)

  • Yoshiki Kawabe

    (Research Division)

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.

Suggested Citation

  • Tatsuya Tamura & Hiroshi Noda & Eri Joyashiki & Maiko Hoshino & Tomoyuki Watanabe & Masahiko Kinosaki & Yoshikazu Nishimura & Tohru Esaki & Kotaro Ogawa & Taiji Miyake & Shinichi Arai & Masaru Shimizu, 2016. "Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13384
    DOI: 10.1038/ncomms13384
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