PMID- 9207935
OWN - NLM
STAT- MEDLINE
DCOM- 19970807
LR  - 20131121
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 40
IP  - 13
DP  - 1997 Jun 20
TI  - Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO 
      donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and 
      toxicity in the liver.
PG  - 1947-54
AB  - We have designed a drug that protects the liver from apoptotic cell death by 
      organ-selective pharmacological generation of the bioregulatory agent, nitric 
      oxide (NO). The discovery strategy involved three steps: identifying a 
      diazeniumdiolate ion (R2N[N(O)NO]-, where R2N = pyrrolidinyl) that spontaneously 
      decomposes to NO with a very short half-life (3 s) at physiological pH; 
      converting this ion to a series of potential prodrug derivatives by covalent 
      attachment of protecting groups that we postulated might be rapidly removed by 
      enzymes prevalent in the liver; and screening the prodrug candidates in vitro and 
      in vivo to select a lead and to confirm the desired activity. Of five cell types 
      examined, only cultured hepatocytes metabolized O2-vinyl 
      1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) to NO, triggering cyclic 
      guanosine 3',5'-monophosphate (cGMP) synthesis and protecting the hepatocytes 
      from apoptotic cell death induced by treatment with tumor necrosis factor-alpha 
      (TNF alpha) plus actinomycin D. In vivo, V-PYRRO/NO increased liver cGMP levels 
      while minimally affecting systemic hemodynamics, protecting rats dosed with TNF 
      alpha plus galactosamine from apoptosis and hepatotoxicity. The results 
      illustrate the potential utility of diazeniumdiolates for targeting NO delivery 
      in vivo and suggest a possible therapeutic strategy for hepatic disorders such as 
      fulminant liver failure.
FAU - Saavedra, J E
AU  - Saavedra JE
AD  - Intramural Research Support Program, SAIC Frederick, NCI-FCRDC, Maryland 21702, 
      USA.
FAU - Billiar, T R
AU  - Billiar TR
FAU - Williams, D L
AU  - Williams DL
FAU - Kim, Y M
AU  - Kim YM
FAU - Watkins, S C
AU  - Watkins SC
FAU - Keefer, L K
AU  - Keefer LK
LA  - eng
GR  - R01-GM-37753/GM/NIGMS NIH HHS/United States
GR  - R01-GM-44100/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate)
RN  - 0 (Prodrugs)
RN  - 0 (Pyrrolidines)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 7535-00-4 (Galactosamine)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Cell Line
MH  - Cyclic GMP/biosynthesis
MH  - DNA Fragmentation/drug effects
MH  - *Drug Delivery Systems
MH  - Drug Design
MH  - Galactosamine/pharmacology
MH  - Hemodynamics/drug effects
MH  - Liver/*drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Nitric Oxide/*administration & dosage/metabolism
MH  - Prodrugs/administration & dosage/*chemical synthesis/pharmacology
MH  - Pyrrolidines/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/pharmacology/toxicity
EDAT- 1997/06/20 00:00
MHDA- 1997/06/20 00:01
CRDT- 1997/06/20 00:00
PHST- 1997/06/20 00:00 [pubmed]
PHST- 1997/06/20 00:01 [medline]
PHST- 1997/06/20 00:00 [entrez]
AID - jm9701031 [pii]
AID - 10.1021/jm9701031 [doi]
PST - ppublish
SO  - J Med Chem. 1997 Jun 20;40(13):1947-54. doi: 10.1021/jm9701031.