title: Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism.
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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Noda
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Joyashiki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Hoshino
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kinosaki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Esaki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Miyake
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Arai
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Hidetomo
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kawabe
mesh_terms: D000818:Animals; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007011:Hypoparathyroidism / Q000188:drug therapy*; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009154:Mutation; D010280:Parathyroid Glands / Q000187:drug effects / Q000601:surgery; D051381:Rats; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D048289:Imidazolidines; C000628187:PCO371; D044168:Receptor, Parathyroid Hormone, Type 1; D013141:Spiro Compounds