Discovery of a Novel Potent and Selective Calcium Release-Activated Calcium Channel Inhibitor: 2,6-Difluoro-N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide. Structure–Activity Relationship and Preclinical Characterization

Autor: Shashikant Pawar, Vinod Patil, Rajender Kumar Kamboj, Milind Sindkhedkar, Trupti Bhankhede, Venkata P. Palle, Jaysagar Gundu, Spinvin Venugopal, Dhananjay Bakhle, Praveenkumar Anidil Kizhakinagath, Kumar Naik, Sanjay Bokan, Zubair Shaikh, Sagar Budhe, Vikas Shinde, Dipak Modi, M. K. Singh, Maneesh Mehta, Kamlesh J Padiya, Gururaj Vishwase, Akshaya Wagh, Rajesh Gupta, Sharad Sharma, Hemant Kumar, Sandip Kuldharan, Sadanand Mallurwar, Neelima Sinha, Gokul Deshmukh, Kaustubh Tamane, Himani Pareek, Rajesh Yeshodharan, Prashant B. Nigade, Milind Gholve, Kumar V S Nemmani, Santosh Jachak, Dilip Pandey, Nidhi Sharma, Vijay Karche, Lakshmi Narasimham, Nageswara Rao Irlapatti, Jagadeesh Daler, Rajesh Shankar, Nilesh Raghunath Khedkar, Mandar Bhonde, Vijay Kanoje, Prabakaran Kamalakannan, Chirag Shah, Shaji K George, Sachin Ingawale, Prajakta Ahirrao, Disha Dadke, Harshal Narendra Nemade, Anil Kalia, Amit Patil, Samiron Phukan, Swaroop Kumar
Rok vydání: 2021
Předmět:
Zdroj: Journal of Medicinal Chemistry. 64:17004-17030
ISSN: 1520-4804
0022-2623
Popis: The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.
Databáze: OpenAIRE
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