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

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 r...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 64; no. 23; pp. 17004 - 17030
Main Authors:	Khedkar, Nilesh Raghunath, Irlapatti, Nageswara Rao, Dadke, Disha, Kanoje, Vijay, Shaikh, Zubair, Karche, Vijay, Shinde, Vikas, Deshmukh, Gokul, Patil, Amit, Jachak, Santosh, Phukan, Samiron, Kizhakinagath, Praveenkumar Anidil, Gholve, Milind, Bhankhede, Trupti, Daler, Jagadeesh, Nemade, Harshal Narendra, Budhe, Sagar, Pareek, Himani, Yeshodharan, Rajesh, Gupta, Rajesh, Kalia, Anil, Pandey, Dilip, Wagh, Akshaya, Kumar, Swaroop, Patil, Vinod, Modi, Dipak, Sharma, Nidhi, Ahirrao, Prajakta, Mehta, Maneesh, Kumar, Hemant, Nigade, Prashant, Tamane, Kaustubh, Mallurwar, Sadanand, Kuldharan, Sandip, Pawar, Shashikant, Vishwase, Gururaj, Bokan, Sanjay, Singh, Minakshi, Naik, Kumar, Ingawale, Sachin, Shankar, Rajesh, Kamalakannan, Prabakaran, Venugopal, Spinvin, George, Shaji K, Padiya, Kamlesh J, Nemmani, Kumar V. S, Gundu, Jaysagar, Bhonde, Mandar, Narasimham, Lakshmi, Sindkhedkar, Milind, Shah, Chirag, Sinha, Neelima, Sharma, Sharad, Bakhle, Dhananjay, Kamboj, Rajender Kumar, Palle, Venkata P
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 09-12-2021
Subjects:	Administration, Oral Animals Area Under Curve Arthritis, Rheumatoid - drug therapy Calcium - metabolism Calcium Channel Blockers - pharmacokinetics Calcium Channel Blockers - pharmacology Calcium Release Activated Calcium Channels - antagonists & inhibitors Clinical Trials, Phase I as Topic Drug Discovery Humans Jurkat Cells Male Mice Mice, Inbred BALB C Rats Rats, Inbred Lew Structure-Activity Relationship
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.1c01403