作者
Shaoyi Sun,Qi Jia,Alla Zenova,Michael Wilson,Sultan Chowdhury,Thilo Focken,Jun Li,Shannon Decker,Michael Grimwood,Jean‐Christophe Andrez,Ivan Hemeon,Tao Sheng,Chien‐An Chen,Andy White,David H. Hackos,Lin Deng,Girish Bankar,Kuldip Khakh,Elaine Chang,Rainbow Kwan,Sophia Lin,Karen Nelkenbrecher,Benjamin D. Sellers,Antonio G. DiPasquale,Jae H. Chang,Jodie Pang,Luis Sojo,Andrea Lindgren,Matthew Waldbrook,Zhiwei Xie,Clint Young,J. P. Johnson,Carole Robinette,Charles J. Cohen,Brian S. Safina,Daniel P. Sutherlin,Daniel F. Ortwine,Christoph M. Dehnhardt
摘要
Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious NaV1.7 inhibitors reported to date.