Design, Synthesis, and Evaluation of Novel Prodrugs of Transition State Inhibitors of Norovirus 3CL Protease
| Autor: | Anushka C. Galasiti Kankanamalage, Steven C. Cardinale, A.D. Rathnayake, Michelle M. Butler, William C. Groutas, Terry L. Bowlin, Yunjeong Kim, Kyeong-Ok Chang, Kevin R. Alliston |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Proteases Pyrrolidines Stereochemistry medicine.medical_treatment 030106 microbiology Cysteine Proteinase Inhibitors Antiviral Agents Aldehyde Cell Line Adduct Mice Structure-Activity Relationship Viral Proteins 03 medical and health sciences Drug Discovery medicine Animals Humans Structure–activity relationship Prodrugs chemistry.chemical_classification Aza Compounds Protease Chemistry Hydrolysis Norovirus Esters Stereoisomerism Blood Proteins Prodrug Bisulfite Cysteine Endopeptidases 030104 developmental biology Microsomes Liver Molecular Medicine Carbamates Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 60:6239-6248 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00497 |
| Popis: | Ester and carbamate prodrugs of aldehyde bisulfite adduct inhibitors were synthesized in order to improve their pharmacokinetic and pharmacodynamic properties. The inhibitory activity of the compounds against norovirus 3C-like protease in enzyme and cell-based assays was determined. The ester and carbamate prodrugs displayed equivalent potency to those of the precursor aldehyde bisulfite adducts and precursor aldehydes. Furthermore, the rate of ester cleavage was found to be dependent on alkyl chain length. The generated prodrugs exhibited low cytotoxicity and satisfactory liver microsomes stability and plasma protein binding. The methodology described herein has wide applicability and can be extended to the bisulfite adducts of common warheads employed in the design of transition state inhibitors of serine and cysteine proteases of medical relevance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|