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Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism.
Shukla, Manojkumar R; Sadasivam, Gayathri; Sarde, Ankush; Sayyed, Majid; Pachpute, Vipul; Phadtare, Ramesh; Walke, Navanath; Chaudhari, Vinod D; Loriya, Rajesh; Khan, Talha; Gote, Ganesh; Pawar, Chetan; Tryambake, Mahadeo; Mahajan, Nilesh; Gandhe, Amruta; Sabde, Sudeep; Pawar, Shashikant; Patil, Vinod; Modi, Dipak; Mehta, Maneesh; Nigade, Prashant; Modak, Vijay; Ghodke, Ravindra; Narasimham, Lakshmi; Bhonde, Mandar; Gundu, Jayasagar; Goel, Rajan; Shah, Chirag; Kulkarni, Sanjeev; Sharma, Sharad; Bakhle, Dhananjay; Kamboj, Rajender Kumar; Palle, Venkata P.
Affiliation
  • 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.
J Med Chem ; 66(14): 9418-9444, 2023 07 27.
Article in En | MEDLINE | ID: mdl-37442941
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 pKa. A systematic optimization of cinacalcet to reduce its cLogP and pKa 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Renal Insufficiency, Chronic / Hyperparathyroidism, Secondary Type of study: Etiology_studies / Prognostic_studies Limits: Animals Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2023 Document type: Article Affiliation country: India
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Renal Insufficiency, Chronic / Hyperparathyroidism, Secondary Type of study: Etiology_studies / Prognostic_studies Limits: Animals Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2023 Document type: Article Affiliation country: India