Novel fluoropeptidomimetics: synthesis, stability studies and protease inhibition.
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.
Annedi
Subhash C
SC
Molecular Design and Information Technology Center, Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2.
Majumder
Kanchana
K
Wei
Lianhu
L
Oyiliagu
Catherine E
CE
Samson
Sheeba
S
Kotra
Lakshmi P
LP
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
D006845:Hydrocarbons, Fluorinated; D010455:Peptides; D011480:Protease Inhibitors; D002918:Chymotrypsin