Effect of potential amine prodrugs of selective neuronal nitric oxide synthase inhibitors on blood-brain barrier penetration.
Several prodrug approaches were taken to mask amino groups in two potent and selective neuronal nitric oxide synthase (nNOS) inhibitors containing either a primary or secondary amino group to lower the charge and improve blood-brain barrier (BBB) penetration. The primary amine was masked as an azide and the secondary amine as an amide or carbamate. The azide was not reduced to the amine under a variety of in vitro and ex vivo conditions. Despite the decrease in charge of the amino group as an amide and as carbamates, BBB penetration did not increase. It appears that the uses of azides as prodrugs for primary amines or amides and carbamates as prodrugs for secondary amines are not universally effective for CNS applications.
Silverman
Richard B
RB
Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, United States. Agman@chem.northwestern.edu
Lawton
Graham R
GR
Ralay Ranaivo
Hantamalala
H
Chico
Laura K
LK
Seo
Jiwon
J
Watterson
D Martin
DM
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009474:Neurons / Q000201:enzymology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000588:Amines; D001386:Azides; D004791:Enzyme Inhibitors; D011355:Prodrugs; D052248:Nitric Oxide Synthase Type I