PMID- 8568809
OWN - NLM
STAT- MEDLINE
DCOM- 19960301
LR  - 20131121
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 39
IP  - 1
DP  - 1996 Jan 5
TI  - Substituted xanthines, pteridinediones, and related compounds as potential 
      antiinflammatory agents. Synthesis and biological evaluation of inhibitors of 
      tumor necrosis factor alpha.
PG  - 2-9
AB  - A series of analogues of pentoxifylline metabolites were prepared in the purine, 
      pteridine, [1,2,5]-thiadiazolo[3,4-d]pyrimidine, and quinazoline ring systems and 
      evaluated for their ability to inhibit the production of tumor necrosis 
      factor-alpha (TNF alpha) in human peripheral blood monocytes stimulated with 
      bacterial lipopolysaccharide (LPS). The more active compounds were also tested 
      for inhibition of cyclic AMP phosphodiesterase type IV (PDE IV) from human 
      neutrophils in order to help determine their mechanism of action. Selected 
      compounds which showed good activity in the in vitro TNF alpha assay were 
      evaluated in an in vivo LPS-induced leukopenia model in mice. The most potent 
      compounds in the TNF alpha assay, 6, 31, and 58, inhibited TNF alpha production 
      at an IC50 of approximately 5 microM for each. Compound 58 was a very poor 
      inhibitor of PDE IV but was the most active at preventing the leukopenia induced 
      by TNF alpha in mice, providing more than 60% protection at 50 mg/kg. Thus, 
      compounds such as 58, which are good inhibitors of TNF alpha production but are 
      devoid of PDE IV inhibitory properties, may have potential as new 
      antiinflammatory agents.
FAU - Cottam, H B
AU  - Cottam HB
AD  - Department of Medicine, University of California, San Diego, La Jolla 92093-0663, 
      USA.
FAU - Shih, H
AU  - Shih H
FAU - Tehrani, L R
AU  - Tehrani LR
FAU - Wasson, D B
AU  - Wasson DB
FAU - Carson, D A
AU  - Carson DA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Pteridines)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Xanthines)
RN  - 29925-17-5 (4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
RN  - EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
RN  - SD6QCT3TSU (Pentoxifylline)
SB  - IM
MH  - *3',5'-Cyclic-AMP Phosphodiesterases
MH  - 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone/pharmacology
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*chemical synthesis/pharmacology
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Leukopenia/prevention & control
MH  - Lipopolysaccharides/pharmacology
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Molecular Structure
MH  - Monocytes/drug effects/metabolism
MH  - Neutrophils/drug effects/metabolism
MH  - Pentoxifylline/analogs & derivatives
MH  - Phosphodiesterase Inhibitors/chemical synthesis/pharmacology
MH  - Phosphoric Diester Hydrolases/metabolism
MH  - Pteridines/*chemical synthesis/pharmacology
MH  - Tumor Necrosis Factor-alpha/analysis/*antagonists & inhibitors
MH  - Xanthines/*chemical synthesis/pharmacology
EDAT- 1996/01/05 00:00
MHDA- 1996/01/05 00:01
CRDT- 1996/01/05 00:00
PHST- 1996/01/05 00:00 [pubmed]
PHST- 1996/01/05 00:01 [medline]
PHST- 1996/01/05 00:00 [entrez]
AID - jm940845j [pii]
AID - 10.1021/jm940845j [doi]
PST - ppublish
SO  - J Med Chem. 1996 Jan 5;39(1):2-9. doi: 10.1021/jm940845j.