Document Detail

N-Phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: structure-activity studies and demonstration of in vivo activity.
MedLine Citation:
PMID:  9667974     Owner:  NLM     Status:  MEDLINE    
Selective inhibition of the neuronal isoform of nitric oxide synthase (NOS) compared to the endothelial and inducible isoforms may be required for treatment of neurological disorders caused by excessive production of nitric oxide. Recently, we described N-(3-(aminomethyl)benzyl)acetamidine (13) as a slow, tight-binding inhibitor, highly selective for human inducible nitric oxide synthase (iNOS). Removal of a single methylene bridge between the amidine nitrogen and phenyl ring to give N-(3-(aminomethyl)phenyl)acetamidine (14) dramatically altered the selectivity to give a neuronal selective nitric oxide synthase (nNOS) inhibitor. Part of this large shift in selectivity was due to 14 being a rapidly reversible inhibitor of iNOS in contrast to the essentially irreversible inhibition of iNOS observed with 13. Structure-activity studies revealed that a basic amine functionality tethered to an aromatic ring and a sterically compact amidine are key pharmacophores for this class of NOS inhibitors. Maximal nNOS inhibition potency was achieved with N-(3-(aminomethyl)phenyl)-2-furanylamidine (77) (Ki-nNOS = 0.006 microM; Ki-eNOS = 0.35 microM; Ki-iNOS = 0.16 microM). Finally, alpha-fluoro-N-(3-(aminomethyl)phenyl)acetamidine (74) (Ki-nNOS = 0. 011 microM; Ki-eNOS = 1.1 microM; Ki-iNOS = 0.48 microM) had excellent brain penetration and inhibited nNOS in a rat brain slice assay as well as in the rat brain (cerebellum) in vivo. Thus, N-phenylamidines should be useful in validating the role of nNOS in neurological disorders.
J L Collins; B G Shearer; J A Oplinger; S Lee; E P Garvey; M Salter; C Duffy; T C Burnette; E S Furfine
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  41     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1998 Jul 
Date Detail:
Created Date:  1998-08-03     Completed Date:  1998-08-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2858-71     Citation Subset:  IM    
Glaxo Wellcome Research and Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA.
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MeSH Terms
Amidines* / chemical synthesis,  chemistry,  pharmacology
Cerebellum / drug effects,  enzymology
Cerebral Cortex / cytology,  drug effects,  enzymology
Enzyme Inhibitors* / chemical synthesis,  chemistry,  pharmacology
Furans* / chemical synthesis,  chemistry,  pharmacology
Isoenzymes / antagonists & inhibitors*
Neurons / drug effects*,  enzymology
Nitric Oxide Synthase / antagonists & inhibitors*
Rats, Wistar
Structure-Activity Relationship
Reg. No./Substance:
0/Amidines; 0/Enzyme Inhibitors; 0/Furans; 0/Isoenzymes; 0/N-(3-(aminomethyl)phenyl)-2-furanylamidine; 0/alpha-fluoro-N-(3-(amimomethyl)phenyl)acetamidine; EC Oxide Synthase

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