Design and synthesis of conformationally restricted eight-Membered ring diketones as potential serine protease inhibitors.
The design of conformationally restricted eight-membered ring diketones as transition state mimics of the mechanism of action of cyclotheonamides on serine proteases is described. Two target compounds are prepared from mutilin, derived from the natural product pleuromutilin. Compound 3 shows significant inhibition of plasmin and urokinase in enzyme rate assays, but an analogue 4 in which the amide moiety has been omitted does not. An X-ray crystal structure of the diketone 3 confirms the conformational predictions made by molecular modelling.
Pearson
Neil D
ND
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park North, Third Avenue, The Pinnacles, Harlow, Essex, UK.
Eggleston
Drake S
DS
Haltiwanger
R Curtis
RC
Hibbs
Martin
M
Laver
Alison J
AJ
Kaura
Arun C
AC
D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001952:Bridged-Ring Compounds; D007659:Ketones; D011083:Polycyclic Compounds; D015842:Serine Proteinase Inhibitors; C475718:mutilin