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.
Hallinan
E Ann
EA
Pharmacia, 4901 Searle Parkway, Skokie, Illinois 60077, USA. eahallinan@comcast.net
Kramer
Steven W
SW
Houdek
Stephen C
SC
Moore
William M
WM
Jerome
Gina M
GM
Spangler
Dale P
DP
Stevens
Anna M
AM
Shieh
Huey S
HS
Manning
Pamela T
PT
Pitzele
Barnett S
BS
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