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

Tatsuya Tamura (), Hiroshi Noda, Eri Joyashiki, Maiko Hoshino, Tomoyuki Watanabe, Masahiko Kinosaki, Yoshikazu Nishimura, Tohru Esaki, Kotaro Ogawa, Taiji Miyake, Shinichi Arai, Masaru Shimizu, Hidetomo Kitamura, Haruhiko Sato and Yoshiki Kawabe
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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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13384

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DOI: 10.1038/ncomms13384

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