Discovery, Synthesis, And Structure-Based Optimization of a Series of N-(tert-Butyl)-2-(N-arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhib

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• 作者：Jon Jacobs ; Valerie Grum-Tokars ; Ya Zhou ; Mark Turlington ; S. Adrian Saldanha ; Peter Chase ; Aimee Eggler ; Eric S. Dawson ; Yahira M. Baez-Santos ; Sakshi Tomar ; Anna M. Mielech ; Susan C. Baker ; Craig W. Lindsley ; Peter Hodder ; Andrew Mesecar ; Shaun R. Stauffer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 24, 2013
• 年：2013
• 卷：56
• 期：2
• 页码：534-546
• 全文大小：637K
• 年卷期：v.56,no.2(January 24, 2013)
• ISSN：1520-4804

文摘

A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure鈥揳ctivity relationships within S_{1鈥?/sub>, S1, and S2 enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.}