Journal of Medicinal Chemistry p. 908 - 927 (2019)
Update date:2022-08-24
Topics:
Sun, Shaoyi
Jia, Qi
Zenova, Alla Y.
Wilson, Michael S.
Chowdhury, Sultan
Focken, Thilo
Li, Jun
Decker, Shannon
Grimwood, Michael E.
Andrez, Jean-Christophe
Hemeon, Ivan
Sheng, Tao
Chen, Chien-An
White, Andy
Hackos, David H.
Deng, Lunbin
Bankar, Girish
Khakh, Kuldip
Chang, Elaine
Kwan, Rainbow
Lin, Sophia
Nelkenbrecher, Karen
Sellers, Benjamin D.
Dipasquale, Antonio G.
Chang, Jae
Pang, Jodie
Sojo, Luis
Lindgren, Andrea
Waldbrook, Matthew
Xie, Zhiwei
Young, Clint
Johnson, James P.
Robinette, C. Lee
Cohen, Charles J.
Safina, Brian S.
Sutherlin, Daniel P.
Ortwine, Daniel F.
Dehnhardt, Christoph M.
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.
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Doi:10.1016/S0040-4039(00)78630-8
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