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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 ( IF 6.8 ) Pub Date : 2021-11-29 , DOI: 10.1021/acs.jmedchem.1c01403 Nilesh Raghunath Khedkar 1 , Nageswara Rao Irlapatti 1 , Disha Dadke 1 , Vijay Kanoje 1 , Zubair Shaikh 1 , Vijay Karche 1 , Vikas Shinde 1 , Gokul Deshmukh 1 , Amit Patil 1 , Santosh Jachak 1 , Samiron Phukan 1 , Praveenkumar Anidil Kizhakinagath 1 , Milind Gholve 1 , Trupti Bhankhede 1 , Jagadeesh Daler 1 , Harshal Narendra Nemade 1 , Sagar Budhe 1 , Himani Pareek 1 , Rajesh Yeshodharan 1 , Rajesh Gupta 1 , Anil Kalia 1 , Dilip Pandey 1 , Akshaya Wagh 1 , Swaroop Kumar 1 , Vinod Patil 1 , Dipak Modi 1 , Nidhi Sharma 1 , Prajakta Ahirrao 1 , Maneesh Mehta 1 , Hemant Kumar 1 , Prashant Nigade 1 , Kaustubh Tamane 1 , Sadanand Mallurwar 1 , Sandip Kuldharan 1 , Shashikant Pawar 1 , Gururaj Vishwase 1 , Sanjay Bokan 1 , Minakshi Singh 1 , Kumar Naik 1 , Sachin Ingawale 1 , Rajesh Shankar 1 , Prabakaran Kamalakannan 1 , Spinvin Venugopal 1 , Shaji K George 1 , Kamlesh J Padiya 1 , Kumar V S Nemmani 1 , Jaysagar Gundu 1 , Mandar Bhonde 1 , Lakshmi Narasimham 1 , Milind Sindkhedkar 1 , Chirag Shah 1 , Neelima Sinha 1 , Sharad Sharma 1 , Dhananjay Bakhle 1 , Rajender Kumar Kamboj 1 , Venkata P Palle 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-29 , DOI: 10.1021/acs.jmedchem.1c01403 Nilesh Raghunath Khedkar 1 , Nageswara Rao Irlapatti 1 , Disha Dadke 1 , Vijay Kanoje 1 , Zubair Shaikh 1 , Vijay Karche 1 , Vikas Shinde 1 , Gokul Deshmukh 1 , Amit Patil 1 , Santosh Jachak 1 , Samiron Phukan 1 , Praveenkumar Anidil Kizhakinagath 1 , Milind Gholve 1 , Trupti Bhankhede 1 , Jagadeesh Daler 1 , Harshal Narendra Nemade 1 , Sagar Budhe 1 , Himani Pareek 1 , Rajesh Yeshodharan 1 , Rajesh Gupta 1 , Anil Kalia 1 , Dilip Pandey 1 , Akshaya Wagh 1 , Swaroop Kumar 1 , Vinod Patil 1 , Dipak Modi 1 , Nidhi Sharma 1 , Prajakta Ahirrao 1 , Maneesh Mehta 1 , Hemant Kumar 1 , Prashant Nigade 1 , Kaustubh Tamane 1 , Sadanand Mallurwar 1 , Sandip Kuldharan 1 , Shashikant Pawar 1 , Gururaj Vishwase 1 , Sanjay Bokan 1 , Minakshi Singh 1 , Kumar Naik 1 , Sachin Ingawale 1 , Rajesh Shankar 1 , Prabakaran Kamalakannan 1 , Spinvin Venugopal 1 , Shaji K George 1 , Kamlesh J Padiya 1 , Kumar V S Nemmani 1 , Jaysagar Gundu 1 , Mandar Bhonde 1 , Lakshmi Narasimham 1 , Milind Sindkhedkar 1 , Chirag Shah 1 , Neelima Sinha 1 , Sharad Sharma 1 , Dhananjay Bakhle 1 , Rajender Kumar Kamboj 1 , Venkata P Palle 1
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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.
中文翻译：
发现一种新型强效和选择性钙释放激活钙通道抑制剂：2,6-Difluoro-N-(2'-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-1,3) ,4-恶二唑-2-基)-[1,1'-联苯]-4-基)苯甲酰胺。结构-活性关系和临床前表征
钙释放激活钙 (CRAC) 通道的作用已得到很好的表征，并且在 T 细胞功能中特别重要。CRAC 通道参与多种自身免疫性疾病的发病机制，使其成为治疗类风湿性关节炎 (RA) 等炎性疾病的有吸引力的治疗靶点。以优化亲脂性为目标的系统性构效关系研究成功地产生了两种先导化合物，36和37。两种化合物都显示出良好的效力和选择性以及显着的药代动力学特征。体内 RA 模型的进一步表征和随后的组织组织病理学评估导致将36 个确定为临床候选者。化合物36显示出出色的安全性，并有足够的安全裕度使其有资格用于人体测试。在健康志愿者的 1 期临床研究中口服给药36例，通过 IL-2 和 TNF-α 水平测量，建立了良好的安全性、耐受性和良好的靶标参与度。
更新日期：2021-12-09
中文翻译：
发现一种新型强效和选择性钙释放激活钙通道抑制剂：2,6-Difluoro-N-(2'-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-1,3) ,4-恶二唑-2-基)-[1,1'-联苯]-4-基)苯甲酰胺。结构-活性关系和临床前表征
钙释放激活钙 (CRAC) 通道的作用已得到很好的表征，并且在 T 细胞功能中特别重要。CRAC 通道参与多种自身免疫性疾病的发病机制，使其成为治疗类风湿性关节炎 (RA) 等炎性疾病的有吸引力的治疗靶点。以优化亲脂性为目标的系统性构效关系研究成功地产生了两种先导化合物，36和37。两种化合物都显示出良好的效力和选择性以及显着的药代动力学特征。体内 RA 模型的进一步表征和随后的组织组织病理学评估导致将36 个确定为临床候选者。化合物36显示出出色的安全性，并有足够的安全裕度使其有资格用于人体测试。在健康志愿者的 1 期临床研究中口服给药36例，通过 IL-2 和 TNF-α 水平测量，建立了良好的安全性、耐受性和良好的靶标参与度。
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