Design, synthesis, and neuraminidase inhibitory activity of GS-4071 analogues that utilize a novel hydrophobic paradigm

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 23; pp. 3425 - 3429
• Main Authors: Hanessian, Stephen, Wang, Jianchio, Montgomery, Debra, Stoll, Vincent, Stewart, Kent D., Kati, Warren, Maring, Clarence, Kempf, Dale, Hutchins, Charles, Laver, W.Graeme
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02.12.2002; Elsevier
• Subjects: Acetamides - chemistry; Acetamides - pharmacology; Amines - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Drug Design; Hydrophobic and Hydrophilic Interactions; Medical sciences; Models, Molecular; Neuraminidase - antagonists & inhibitors; Oseltamivir; Pharmacology. Drug treatments; Structure-Activity Relationship; Vinyl Compounds - chemistry; Enzyme; Enzyme inhibitor; Orthomyxoviridae; Aminoether; In vitro; Influenzavirus; Virus; Structure activity relation; Glycosidases; Aminoacid; Exo-α-sialidase; Hydrolases; Antiviral; Hydrophobic group; Chemical synthesis; O-Glycosidases; Ethylenic compound
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00732-1

Structure-based design has led to the synthesis of a novel analogue of GS-4071, an influenza neuraminidase inhibitor, in which the basic amino group has been replaced by a hydrophobic vinyl group. An X-ray co-crystal structure of the new inhibitor ( K i=45 nM) bound to the active site shows that the vinyl group occupies the same subsite as the amino group in GS-4071. Graphic