PCO371是一种具有口服活性的小分子PTHR1完全激动剂，PCO371结合在PTH1R与Gs蛋白的胞内界面上。
Cas No.:1613373-33-3
Sample solution is provided at 25 µL, 10mM.
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PCO371 is an orally active small-molecule full agonist of the PTHR1, which binds to the intracellular interface of PTH1R and the Gs protein[1-2]. PCO371 can be used in research on PTH-related diseases such as hypoparathyroidism[3].
In vitro, PCO371 (0.1nM–0.1mM) stimulated COS-7 cells expressing human PTH1R and UMR-106 rat osteosarcoma cells expressing endogenous rat PTH1R for 20 minutes or 6 hours. PCO371 dose-dependently stimulated intracellular cAMP production and activated the phospholipase C signaling pathway. PCO371 dose-dependently increased the mRNA expression of Fos, osteocalcin, and RANKL, and decreased the mRNA expression of osteoprotegerin and sclerostin[4]. PCO371 (10nM–100μM) treated LLC-PK1 cells stably expressing the human parathyroid hormone 1 receptor (hPTHR1) for 5-120 minutes. PCO371 activated the receptor in a concentration-dependent manner and increased intracellular cAMP production[5].
In vivo, PCO371 (30mg/kg orally; once daily) was administered for 12 weeks to 32-week-old ovariectomized rats. PCO371 significantly increased bone turnover markers. PCO371 had limited effects on improving bone mineral density and bone strength[4]. A single oral administration of PCO371 (30mg/kg) was given to thyroparathyroidectomized (TPTX) rats. PCO371 significantly increased serum calcium concentration and decreased serum phosphate concentration in mice[5].
References:
[1] Zhao LH, He Q, Yuan Q, et al. Conserved class B GPCR activation by a biased intracellular agonist. Nature. 2023 Sep;621(7979):635-641.
[2] Kobayashi K, Kawakami K, Kusakizako T, et al. Class B1 GPCR activation by an intracellular agonist. Nature. 2023 Jun;618(7967):1085-1093.
[3] Nishimura Y, Esaki T, Isshiki Y, et al. Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety. ChemMedChem. 2024 Mar 1;19(5):e202300589.
[4] Tamura T, Noda H, Joyashiki E, et al. Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism. Nat Commun. 2016 Nov 18;7:13384.
[5] Nishimura Y, Esaki T, Isshiki Y, et al. Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist. J Med Chem. 2020 May 28;63(10):5089-5099.
PCO371是一种具有口服活性的小分子PTHR1完全激动剂，PCO371结合在PTH1R与Gs蛋白的胞内界面上[1-2]。PCO371可用于甲状旁腺功能减退症等PTH相关疾病的研究[3]。
在体外，PCO371（0.1nM–0.1mM）刺激表达人PTH1R的COS-7细胞、表达内源性大鼠PTH1R的UMR-106大鼠骨肉瘤细胞20分钟或6小时。PCO371可剂量依赖性地刺激细胞内cAMP的产生，并激活磷脂酶C信号通路。PCO371可剂量依赖性地增加Fos、骨钙素和RANKL的mRNA表达，并降低骨保护素和骨硬化蛋白的mRNA表达[4]。PCO371（10nM–100μM）处理稳定表达人甲状旁腺激素1型受体（hPTHR1）的LLC-PK1细胞5-120分钟。PCO371以浓度依赖的方式激活受体并增加细胞内的cAMP产量[5]。
在体内，PCO371（30mg/kg口服；每日一次）处理12周，用于32周龄的卵巢切除大鼠，PCO371显著增加了骨转换指标。PCO371对骨密度和骨强度的提升作用有限[4]。PCO371（30mg/kg）单次口服给药，用于处理甲状腺甲状旁腺切除（TPTX）大鼠。PCO371显著增加了小鼠的血清钙浓度并降低了血清磷酸盐浓度[5]。
| Cell experiment [1]: | |
Cell lines | COS-7 cells (monkey kidney fibroblast-like cell line), UMR-106 cells (rat osteosarcoma cell line) |
Preparation Method | COS-7 cells were transfected to express human PTHR1 (hPTHR1). Cells were treated with PCO371 (0.1nM–0.1mM) in assay medium containing BSA and the phosphodiesterase inhibitor IBMX. UMR-106 cells expressing endogenous rat PTHR1 were also treated with PCO371 in similar assay medium for cAMP measurement or in DMEM with 0.2% BSA for gene expression analysis. |
Reaction Conditions | 0.1nM–0.1mM; 20 minutes or 6h |
Applications | PCO371 dose-dependently stimulated cAMP production in hPTHR1-expressing COS-7 cells (EC₅₀=2.4μM) and also activated the phospholipase C signaling pathway (EC₅₀=17μM). In UMR-106 cells, PCO371 induced cAMP production and altered the expression of bone-related mRNAs. |
| Animal experiment [2]: | |
Animal models | Thyroparathyroidectomized (TPTX) rats |
Preparation Method | TPTX rats with serum calcium levels <8.0mg/dL received a single oral administration of PCO371 (30mg/kg). Blood was collected from the jugular vein immediately before and at 0.5, 1, 2, 4, 6, 10, and 24 hours after administration to measure serum calcium and phosphate levels. |
Dosage form | 30mg/kg; p.o.; Single administration. |
Applications | A single oral administration of PCO371 dose-dependently increased serum calcium concentration and decreased serum phosphate concentration. The calcemic action of PCO371 was more prolonged than that of its lead compound or a single subcutaneous administration of hPTH(1-34). |
References: | |
| Cas No. | 1613373-33-3 | SDF | |
| Canonical SMILES | FC(F)(F)OC1=CC=C(C2=NC3(CCN(S(CCC4=C(C)C=C(N5C(NC(C5(C)C)=O)=O)C=C4C)(=O)=O)CC3)C(N2)=O)C=C1 | ||
| 分子式 | C29H32F3N5O6S | 分子量 | 635.65 |
| 溶解度 | DMSO: 125 mg/mL (196.65 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.5732 mL | 7.866 mL | 15.7319 mL |
| 5 mM | 314.6 μL | 1.5732 mL | 3.1464 mL |
| 10 mM | 157.3 μL | 786.6 μL | 1.5732 mL |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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- Purity: >95.00% Appearance: A solid
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