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]。