Purine nucleoside phosphorylase inhibitors: biochemical and pharmacological studies with 9-benzyl-9-deazaguanine and related compounds.
Certain derivatives of 9-deazaguanine that contain arylmethyl, heteroarylmethyl or cycloalkylmethyl groups at the 9-position are potent inhibitors of purine nucleoside phosphorylase (PNP, E.C. 2.4.2.1). To determine whether these agents can produce metabolically significant inhibition of PNP in cells and in animals, the authors performed pharmacological studies with a representative member of the series, 9-benzyl-9-deazaguanine (BzDAG). BzDAG was a potent inhibitor of PNP from calf spleen (Ki = 12 nM). It was also an effective inhibitor of PNP in cells and in animals as shown by the findings that it 1) inhibited the conversion of inosine to nucleotides in L1210 cells in culture at concentrations that had little effect on the utilization of hypoxanthine; 2) potentiated the toxicity of deoxyguanosine to CCRF-CEM cells in culture; 3) increased the pools of deoxy GTP in CCRF-CEM, Molt-3 and Molt-4 cells that had been treated with deoxyguanosine; 4) prevented the toxicity of 6-thioguanosine to HEp-2 cells in culture; 5) increased the plasma levels of endogenous inosine in rats; and 6) increased the plasma levels of 2',3'-dideoxyinosine in rats that had received BzDAG and dideoxyinosine in combination. Pharmacokinetic analysis of BzDAG in the rat showed it to be 48% orally bioavailable (at a dose of 5 mg/kg). About 95% of BzDAG was protein bound. After i.v. administration of BzDAG (5 mg/kg), more than 50% of the erythrocyte PNP was inhibited for 40 min. These results indicate that the 9-substituted-9-deazaguanines are potent orally active PNP inhibitors and are therefore of potential clinical interest as immunosuppressive and anti-inflammatory agents.
Bennett
L L
LL
Ketering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama.
Allan
P W
PW
Noker
P E
PE
Rose
L M
LM
Niwas
S
S
Montgomery
J A
JA
Erion
M D
MD
D000818:Animals; D001593:Benzyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D007288:Inosine / Q000378:metabolism; D007939:Leukemia L1210 / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D051381:Rats; D011917:Rats, Inbred Lew; D013872:Thionucleosides / Q000494:pharmacology
D001593:Benzyl Compounds; D001798:Blood Proteins; D013872:Thionucleosides; D006151:Guanosine; C082660:9-benzyl-9-deazaguanine; D007288:Inosine; D006147:Guanine; C076777:9-deazaguanine; C005783:6-thioguanosine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine