4-Fluorinated L-lysine analogs as selective i-NOS inhibitors: methodology for introducing fluorine into the lysine side chain.
In the literature, the introduction of fluorine into bioactive molecules has been known to enhance the biological activity relative to the parent molecule. Described in this article is the synthesis of 4R-fluoro-L-NIL (12) and 4,4-difluoro-L-NIL (23) as part of our iNOS program. Both 12 and 23 were found to be selective iNOS inhibitors as shown in Table 2 below. Secondarily, methodology to synthesize orthogonally protected 4-fluoro-L-lysine and 4,4-difluoro-L-lysine has been developed.
Pharmacia, 4901 Searle Parkway, Skokie, Illinois 60077, USA. eahallinan@comcast.net
E Ann
EA
Hallinan
Steven W
SW
Kramer
Stephen C
SC
Houdek
William M
WM
Moore
Gina M
GM
Jerome
Dale P
DP
Spangler
Anna M
AM
Stevens
Huey S
HS
Shieh
Pamela T
PT
Manning
Barnett S
BS
Pitzele
D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II
D004791:Enzyme Inhibitors; D005461:Fluorine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine