SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Plewe, Michael B.¹  Whitby, Landon R.²  Naik, Shibani¹  Brown, Eric R.¹  Sokolova, Nadezda, V¹  Gantla, Vidyasagar Reddy¹  York, Joanne⁴  Nunberg, Jack H.⁴  Zhang, Lihong⁵  Kalveram, Birte⁵  Freiberg, Alexander N.^5,6  Boger, Dale L.^2,3  Henkel, Greg¹  McCormack, Ken¹ 

[1] Arisan Therapeut, 11189 Sorrento Valley Rd,Suite 104, San Diego, CA 92054 USA

[2] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[4] Univ Montana, Montana Biotechnol Ctr, Missoula, MT 59812 USA

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

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

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

DOI  :  10.1016/j.bmcl.2019.08.024

来源: Elsevier

【 摘 要 】

Old World (Africa) and New World (South America) arenaviruses are associated with human hemorrhagic fevers. Efforts to develop small molecule therapeutics have yielded several chemical series including the 4-acyl-1,6-dialkylpiperazin-2-ones. Herein, we describe an extensive exploration of this chemotype. In initial Phase I studies, R-1 and R-4 scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R-6 substituents and iterative R-1, R-4 and R-6 substituent combinations were evaluated to obtain compounds with improved Lassa and New World (Machupo, Junin, and Tacaribe) arenavirus inhibitory activity, in vitro human liver microsome metabolic stability and aqueous solubility.

【 授权许可】

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