2023•Journal of Medicinal ChemistryRequires access
Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism
Manojkumar R. Shukla, Gayathri Sadasivam, Ankush Sarde, Majid Sayyed, Vipul Pachpute, Ramesh Phadtare, Navanath Walke, Vinod D. Chaudhari, Rajesh Loriya, Talha Khan, Ganesh Gote, Chetan Pawar, Mahadeo Tryambake, Nilesh Manoharrao Mahajan, Amruta Gandhe, Sudeep Sabde, Shashikant S. Pawar, Vinod Shivagouda Patil, Dipak Modi, Maneesh Mehta, Prashant B. Nigade, Vijay Modak, Ravindra Ghodke, Lakshmi Narasimham, Mandar Bhonde, Jayasagar Gundu, Rajan Naresh Goel, Chirag Shah, Sanjeev Kulkarni, Sharad Sharma, Dhananjay Bakhle, Rajender Kumar Kamboj, Venkata P. Palle
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Abstract
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 K a . A systematic optimization of cinacalcet to reduce its cLogP and p K a yielded compound 23a (LNP1892). Compound 23a 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, 23a 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 23a 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.