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DOI 10.1021/acs.jmedchem.1c01403

Медицинская библиотека · Journal of medicinal chemistry · 2021

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.

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

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Аннотация

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.

Для цитирования: 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. 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.. Journal of medicinal chemistry. 2021. DOI: 10.1021/acs.jmedchem.1c01403.

Предметные рубрики MeSH

Administration, OralAnimalsArea Under CurveArthritis, RheumatoidCalciumCalcium Channel BlockersCalcium Release Activated Calcium ChannelsClinical Trials, Phase I as TopicDrug DiscoveryHumansJurkat CellsMaleMiceMice, Inbred BALB CRatsRats, Inbred LewStructure-Activity Relationship
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