Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
J Med Chem. 2023 Jul 27;66(14):9418-9444. doi: 10.1021/acs.jmedchem.3c00698. Epub 2023 Jul 13.
The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and p. A systematic optimization of cinacalcet to reduce its cLogP and p yielded compound (LNP1892). Compound showed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, demonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with in healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.
钙敏感受体（CaSR）在维持钙稳态中发挥着重要作用。使用拟钙剂西那卡塞激活 CaSR 以纠正高钙血症已得到广泛应用。然而，由于西那卡塞具有较高的 cLogP 和 p 值，其应用受到限制。通过对西那卡塞进行系统优化以降低其 cLogP 和 p 值，得到了化合物 （LNP1892）。化合物 显示出优异的效力和良好的药代动力学特征，并且缺乏西那卡塞的不良反应，使其成为一种高度差异化的精准拟钙剂。在腺嘌呤饮食诱导的慢性肾脏病（CKD）模型中，化合物 表现出强大且呈剂量依赖性的疗效，可通过血浆甲状旁腺激素（PTH）水平来衡量。在动物研究中也显示出了出色的安全性。在健康志愿者中进行的 Ⅰ期临床试验证实了其良好的安全性、耐受性和有效性，能够以剂量依赖性方式降低 PTH 水平，而不会导致症状性低钙血症。这些有前途的结果促使 LNP1892 进入 CKD 患者的 Ⅱ期研究。
