β-Lactam Derivatives as Inhibitors of Human Cytomegalovirus Protease

• Published in: Journal of medicinal chemistry Vol. 41; no. 15; pp. 2882 - 2891
• Main Authors: Yoakim, Christiane, Ogilvie, William W, Cameron, Dale R, Chabot, Catherine, Guse, Ingrid, Haché, Bruno, Naud, Julie, O'Meara, Jeff A, Plante, Raymond, Déziel, Robert
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.07.1998; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; beta-Lactams - chemical synthesis; beta-Lactams - chemistry; beta-Lactams - pharmacology; Biological and medical sciences; Cattle; Cell Line, Transformed; Chemistry, Medicinal; Cytomegalovirus - drug effects; Cytomegalovirus - enzymology; Cytomegalovirus - physiology; Human cytomegalovirus; Humans; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; plaque reduction assay; Science & Technology; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Swine; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology; E-I-COMPLEXES; DOMAIN; MECHANISM; GENE; AM1; STABILITY; HUMAN-LEUKOCYTE ELASTASE; STEREOSPECIFIC SYNTHESIS; Four membered ring; Enzyme; Nitrogen heterocycle; Herpesviridae; Lactam; Enzyme inhibitor; Betaherpesvirinae; In vitro; Human cytomegalovirus; Pyridine derivatives; Virus; Peptidases; Structure activity relation; Benzylic compound; Azetidine derivatives; Hydrolases; Antiviral; Ureas; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980131z

The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the β-lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both tri- and tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.