N(G)-aminoguanidines from primary amines and the preparation of nitric oxide synthase inhibitors.
A concise, general, and high-yielding method for the preparation of N(G)-aminoguanidines from primary amines is reported. Using available and readily prepared materials, primary amines are converted to protected N(G)-aminoguanidines in a one-pot procedure. The method has been successfully applied to a number of examples including the syntheses of four nitric oxide synthase (NOS) inhibitors. The inhibitors prepared were investigated as competitive inhibitors and as mechanistic inactivators of the inducible isoform of NOS (iNOS). In addition, one of the four inhibitors prepared, N(G)-amino-N(G)-2,2,2-trifluoroethyl-L-arginine 19, displays the unique ability to both inhibit NO formation and prevent NADPH consumption by iNOS without irreversible inactivation of the enzyme.
Martin
Nathaniel I
NI
Department of Chemistry,Division of Physical Sciences, Lawrence Berkeley National Laboratory, University of California, Berkeley 94720-3220, USA.
Beeson
William T
WT
Woodward
Joshua J
JJ
Marletta
Michael A
MA
D000588:Amines / Q000737:chemistry*; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry; D009249:NADP / Q000737:chemistry; D009569:Nitric Oxide / Q000138:chemical synthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000737:chemistry; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D006146:Guanidines; C528856:N(G)-amino-N(G)-2,2,2-trifluoroethylarginine; D009569:Nitric Oxide; D009249:NADP; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II