Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:41

Article

Plewe, Michael B.^1,4  Gantla, Vidyasagar Reddy¹  Sokolova, Nadezda, V¹  Shin, Young-Jun¹  Naik, Shibani¹  Brown, Eric R.¹  Fetsko, Alexandra¹  Zhang, Lihong^2,3  Kalveram, Birte^2,3  Freiberg, Alexander N.^2,3  Henkel, Greg¹  McCormack, Ken¹ 

[1] Arisan Therapeut, 11189 Sorrento Valley Rd,Suite 104, San Diego, CA 92121 USA

[2] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA

[3] Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA

[4] Cullgen USA Inc, 12671 High Bluff Dr,Suite 130, San Diego, CA 92130 USA

关键词: Arenavirus;    Lassa;    Junin;    Machupo;    Entry inhibitor;   

DOI  :  10.1016/j.bmcl.2021.127983

来源: Elsevier

【 摘 要 】

We identified and explored the structure?activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e.g., the simple high yield 3-step synthesis of imidazo[1,2-a]pyridine 37) could provide a cost-effective broad-spectrum arenavirus therapeutic that may help to minimize the costprohibitive burdens associated with treatments for emerging viruses in economically challenged geographical settings.

【 授权许可】

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