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Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.
Ramdas, Vidya; Talwar, Rashmi; Kanoje, Vijay; Loriya, Rajesh M; Banerjee, Moloy; Patil, Pradeep; Joshi, Advait Arun; Datrange, Laxmikant; Das, Amit Kumar; Walke, Deepak Sahebrao; Kalhapure, Vaibhav; Khan, Talha; Gote, Ganesh; Dhayagude, Usha; Deshpande, Shreyas; Shaikh, Javed; Chaure, Ganesh; Pal, Ravindra R; Parkale, Santosh; Suravase, Sachin; Bhoskar, Smita; Gupta, Rajesh V; Kalia, Anil; Yeshodharan, Rajesh; Azhar, Mahammad; Daler, Jagadeesh; Mali, Vinod; Sharma, Geetika; Kishore, Amitesh; Vyawahare, Rupali; Agarwal, Gautam; Pareek, Himani; Budhe, Sagar; Nayak, Arun; Warude, Dnyaneshwar; Gupta, Praveen Kumar; Joshi, Parag; Joshi, Sneha; Darekar, Sagar; Pandey, Dilip; Wagh, Akshaya; Nigade, Prashant B; Mehta, Maneesh; Patil, Vinod; Modi, Dipak; Pawar, Shashikant; Verma, Mahip; Singh, Minakshi; Das, Sudipto; Gundu, Jayasagar.
Afiliación
  • Ramdas V; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Talwar R; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Kanoje V; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Loriya RM; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Banerjee M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Patil P; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Joshi AA; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Datrange L; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Das AK; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Walke DS; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Kalhapure V; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Khan T; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Gote G; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Dhayagude U; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Deshpande S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Shaikh J; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Chaure G; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Pal RR; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Parkale S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Suravase S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Bhoskar S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Gupta RV; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Kalia A; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Yeshodharan R; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Azhar M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Daler J; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Mali V; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Sharma G; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Kishore A; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Vyawahare R; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Agarwal G; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Pareek H; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Budhe S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Nayak A; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Warude D; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Gupta PK; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Joshi P; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Joshi S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Darekar S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Pandey D; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Wagh A; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Nigade PB; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Mehta M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Patil V; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Modi D; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Pawar S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Verma M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Singh M; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Das S; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
  • Gundu J; Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
J Med Chem ; 63(11): 6107-6133, 2020 06 11.
Article en En | MEDLINE | ID: mdl-32368909
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Cromanos / Canal de Sodio Activado por Voltaje NAV1.7 / Bloqueadores del Canal de Sodio Activado por Voltaje Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: India Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Cromanos / Canal de Sodio Activado por Voltaje NAV1.7 / Bloqueadores del Canal de Sodio Activado por Voltaje Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: India Pais de publicación: Estados Unidos