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

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–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.


Related in: MedlinePlus

Synthesis of compound 9.Reagents and conditions: (g) 2-bromoisobutyric acid, DIPEA, DMI, 100 °C; (h) 5 mol l−1 NaOH aq., MeOH, 75 °C; (i) NaOCN, AcOH, CH2Cl2, room temperature.
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f8: Synthesis of compound 9.Reagents and conditions: (g) 2-bromoisobutyric acid, DIPEA, DMI, 100 °C; (h) 5 mol l−1 NaOH aq., MeOH, 75 °C; (i) NaOCN, AcOH, CH2Cl2, room temperature.

Mentions: A mixture of 4-bromo-3,5-dimethylaniline (7) (3.47 g, 17.3 mmol), DIPEA (5.3 ml, 30.4 mmol) and 2-bromoisobutyric acid (3.86 g, 23.1 mmol) in anhydrous DMI (13 ml) was stirred at 100 °C for 1 h under N2 (Fig. 8). Then additional 2-bromoisobutyric acid (496 mg, 2.97 mmol) and iPr2EtN (0.80 ml, 4.59 mmol) was added, and the mixture was stirred at 100 °C for 1 h under N2. The mixture was cooled to room temperature, and MeOH (52 ml) and 5 mol l−1 NaOH aq. (52 ml, 260 mmol) were added. This mixture was stirred at 75 °C for 1.5 h and acidified with 1 mol l−1 KHSO4 aq. (pH 5) at 0 °C, diluted with H2O, and the product was extracted with EtOAc. The organic layer was washed with H2O, dried over anhydrous MgSO4 and evaporated in vacuo to afford compound 8 (5.79 g, crude). This crude mixture was used in the next step without further purification.


Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism
Synthesis of compound 9.Reagents and conditions: (g) 2-bromoisobutyric acid, DIPEA, DMI, 100 °C; (h) 5 mol l−1 NaOH aq., MeOH, 75 °C; (i) NaOCN, AcOH, CH2Cl2, room temperature.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Synthesis of compound 9.Reagents and conditions: (g) 2-bromoisobutyric acid, DIPEA, DMI, 100 °C; (h) 5 mol l−1 NaOH aq., MeOH, 75 °C; (i) NaOCN, AcOH, CH2Cl2, room temperature.
Mentions: A mixture of 4-bromo-3,5-dimethylaniline (7) (3.47 g, 17.3 mmol), DIPEA (5.3 ml, 30.4 mmol) and 2-bromoisobutyric acid (3.86 g, 23.1 mmol) in anhydrous DMI (13 ml) was stirred at 100 °C for 1 h under N2 (Fig. 8). Then additional 2-bromoisobutyric acid (496 mg, 2.97 mmol) and iPr2EtN (0.80 ml, 4.59 mmol) was added, and the mixture was stirred at 100 °C for 1 h under N2. The mixture was cooled to room temperature, and MeOH (52 ml) and 5 mol l−1 NaOH aq. (52 ml, 260 mmol) were added. This mixture was stirred at 75 °C for 1.5 h and acidified with 1 mol l−1 KHSO4 aq. (pH 5) at 0 °C, diluted with H2O, and the product was extracted with EtOAc. The organic layer was washed with H2O, dried over anhydrous MgSO4 and evaporated in vacuo to afford compound 8 (5.79 g, crude). This crude mixture was used in the next step without further purification.

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–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.


Related in: MedlinePlus