Novel fluoropeptidomimetics: synthesis, stability studies and protease inhibition

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 8; pp. 2943 - 2958
• Main Authors: Annedi, Subhash C., Majumder, Kanchana, Wei, Lianhu, Oyiliagu, Catherine E., Samson, Sheeba, Kotra, Lakshmi P.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.04.2005; Elsevier Science
• Subjects: Biological and medical sciences; Chemistry and aqueous stability; Chymotrypsin - antagonists & inhibitors; Computer Simulation; Crystallography, X-Ray; Drug Design; Enzyme Activation; Fluoropeptidomimetics; Hydrocarbons, Fluorinated - chemical synthesis; Hydrocarbons, Fluorinated - chemistry; Hydrocarbons, Fluorinated - pharmacology; Medical sciences; Miscellaneous; Models, Molecular; Molecular Mimicry; Molecular Structure; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Pharmacology. Drug treatments; Protease inhibitors; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Stereoisomerism; Structure-Activity Relationship; Protease inhibitors; Chemistry and aqueous stability; Fluoropeptidomimetics; Stability; Serine endopeptidases; Peptides; Enzyme; Peptidomimetic compound; Enzyme inhibitor; Biological activity; Chymotrypsin; Peptidases; Cyclization; Hydrolases; Fluorine Organic compounds; Aqueous solution; Chemical synthesis; Oxazole derivatives; Protease inhibitor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.02.011

[Display omitted] Designer fluoropeptidomimetics as protease inhibitors are revealed. The key peptidomimetic region in the inhibitors contains a ‘–CHF–S–’ moiety and is designed to mimic the tetrahedral oxyanion species during the hydrolysis of a peptide bond. Designed fluoropeptidomimetics in aqueous methanol slowly (in several hours to days) yielded the corresponding methyl ether and/or the oxazole derivatives after cyclization. Alkyl substitutions at the C-2 position exhibited enhanced aqueous stability. Nature of ‘–CHF–S–’ moiety and the stabilities of various fluoropeptidomimetics in aqueous solution are disclosed in detail. Fluoropeptidomimetics containing bulky substitutions at P1 such as compounds 15 and 16 exhibited time-dependent loss of activities against chymotrypsin, up to 67% and 79% with a K i of 63 and 120 μM, respectively. Fluoropeptidomimetics are a novel class of protease inhibitors and the next generation of fluoropeptidomimetics should incorporate enhanced stability.