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

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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.

No MeSH data available.


Effects of PCO371 on 45Ca release from pre-labelled fetal rat long bones.Control medium contained only vehicle for PCO371 (0.1% DMSO) or hPTH(1–34) (10 μmol l−1 acetic acid). Data are represented as the mean+s.d. of one experiment (n=4). Williams's test was used to compare PCO371- or hPTH(1–34)-treated groups with vehicle-treated group; **P<0.01, ***P<0.001.
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f3: Effects of PCO371 on 45Ca release from pre-labelled fetal rat long bones.Control medium contained only vehicle for PCO371 (0.1% DMSO) or hPTH(1–34) (10 μmol l−1 acetic acid). Data are represented as the mean+s.d. of one experiment (n=4). Williams's test was used to compare PCO371- or hPTH(1–34)-treated groups with vehicle-treated group; **P<0.01, ***P<0.001.

Mentions: We next examined whether PCO371 induces PTH-like bone-resorbing activity in organ cultures with fetal rat long bones. PCO371 at 1 μmol l−1 or more had the ability to stimulate 45Ca release from prelabeled bones as did hPTH(1–34) (Fig. 3).


Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism
Effects of PCO371 on 45Ca release from pre-labelled fetal rat long bones.Control medium contained only vehicle for PCO371 (0.1% DMSO) or hPTH(1–34) (10 μmol l−1 acetic acid). Data are represented as the mean+s.d. of one experiment (n=4). Williams's test was used to compare PCO371- or hPTH(1–34)-treated groups with vehicle-treated group; **P<0.01, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120204&req=5

f3: Effects of PCO371 on 45Ca release from pre-labelled fetal rat long bones.Control medium contained only vehicle for PCO371 (0.1% DMSO) or hPTH(1–34) (10 μmol l−1 acetic acid). Data are represented as the mean+s.d. of one experiment (n=4). Williams's test was used to compare PCO371- or hPTH(1–34)-treated groups with vehicle-treated group; **P<0.01, ***P<0.001.
Mentions: We next examined whether PCO371 induces PTH-like bone-resorbing activity in organ cultures with fetal rat long bones. PCO371 at 1 μmol l−1 or more had the ability to stimulate 45Ca release from prelabeled bones as did hPTH(1–34) (Fig. 3).

View Article: PubMed Central - PubMed

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&ndash;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.

No MeSH data available.