Novel inhibitors of neuronal nitric oxide synthase with potent antioxidant properties.
A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.
Auvin
Serge
S
Department of Medicinal Chemistry, Beaufour-Ipsen Research Laboratories, Institut Henri Beaufour, 5, Avenue du Canada, 91966 Les Ulis Cedex, France. serge.auvin@beaufour-ipsen.com
Auguet
Michel
M
Navet
Edith
E
Harnett
Jeremiah J
JJ
Viossat
Isabelle
I
Schulz
Jocelyne
J
Bigg
Dennis
D
Chabrier
Pierre E
PE
D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D015742:Propofol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D013379:Substrate Specificity
D000975:Antioxidants; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D015742:Propofol