作者
Ramdas Vidya,Rashmi Talwar,Vijay Kanoje,Rajesh Loriya,Moloy Banerjee,Pradeep Patil,Advait A. Joshi,Laxmikant Datrange,Amit Kumar Das,Deepak Sahebrao Walke,Vaibhav Kalhapure,Talha Ali Khan,Ganesh Gote,Usha Dhayagude,Shreyas Deshpande,J. Shaikh,Ganesh Chaure,Ravindra Pal,Santosh Parkale,Sachin Suravase,Smita Bhoskar,Rajesh V. Gupta,Anil Kalia,Rajesh Yeshodharan,Mahammad Azhar,Jagadeesh Daler,Vinod Mali,Geetika Sharma,A. Sairam Kishore,Rupali Vyawahare,Gautam Agarwal,Himani Pareek,Sagar Budhe,Arun K. Nayak,Dnyaneshwar Warude,Praveen Kumar Gupta,Parag Joshi,Shashank Joshi,Sagar Darekar,Dilip K. Pandey,Akshaya Wagh,Prashant B. Nigade,Maneesh Mehta,Vinod Patil,Dipak Modi,Shashikant Pawar,Mahip K. Verma,Minakshi Singh,Sudipto Das,Jayasagar Gundu,Kumar V.S. Nemmani,Mark G. Bock,Sharad Sharma,Dhananjay Bakhle,Rajender K. Kamboj,Venkata P. Palle
摘要
Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.