Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism.

Autor:	Shukla MR; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Sadasivam G; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Sarde A; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Sayyed M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Pachpute V; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Phadtare R; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Walke N; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Chaudhari VD; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Loriya R; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Khan T; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Gote G; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Pawar C; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Tryambake M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Mahajan N; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Gandhe A; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Sabde S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Pawar S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Patil V; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Modi D; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Mehta M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Nigade P; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Modak V; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Ghodke R; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Narasimham L; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Bhonde M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Gundu J; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Goel R; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Shah C; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Kulkarni S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Sharma S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Bakhle D; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Kamboj RK; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India., Palle VP; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Jul 27; Vol. 66 (14), pp. 9418-9444. Date of Electronic Publication: 2023 Jul 13.
DOI:	10.1021/acs.jmedchem.3c00698
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu