title: Novel fluoropeptidomimetics: synthesis, stability studies and protease inhibition.
abstract: 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, upto [corrected] 67% and 79% with a Ki of 63 and 120 microM, respectively. Fluoropeptidomimetics are a novel class of protease inhibitors and the next generation of fluoropeptidomimetics should incorporate enhanced stability.
authors.affiliation: Molecular Design and Information Technology Center, Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Annedi
authors.forename: Kanchana
authors.initials: K
authors.lastname: Majumder
authors.forename: Lianhu
authors.initials: L
authors.lastname: Wei
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Oyiliagu
authors.forename: Sheeba
authors.initials: S
authors.lastname: Samson
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D006845:Hydrocarbons, Fluorinated; D010455:Peptides; D011480:Protease Inhibitors; D002918:Chymotrypsin