Comparative in vitro and in vivo activities of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase, CI-972 and PD 141955.
An in-parallel comparison is presented of the in vitro and in vivo properties of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase (PNP), CI-972 [8-amino-9-deaza-9-(3-thienylmethyl)guanine] and PD 141955 [9-deaza-9-(3-thienylmethyl)guanine] (published Ki values of 0.83-8.0 and 0.08 microM, respectively). Despite structural similarities, PD 141955 was considerably more potent and active in all systems studied. The respective IC50 values for inhibition of MOLT-4 cell growth in the absence and presence of 10 microM 2'-deoxyguanosine (GdR) were greater than 50 and 5.06 microM for CI-972 and 15.4 and 0.061 microM for PD 141955. PD 141955 induced accumulation of dGTP in GdR-treated MOLT-4 and CEM cells at log-lower concentrations than were required of CI-972, and the magnitude of dGTP accumulation in PD 141955-treated T cell cultures was markedly greater (e.g. 366 vs 100 pmol/10(6) CEM cells at 10 microM). PD 141955 administered orally produced a dose-dependent elevation of plasma inosine and guanosine in rats over a broad concentration range. Mean plasma inosine concentrations following a 150 mg/kg p.o. dose peaked at 6.21 and 13.2 microM in CI-972 and PD 141955-treated rats, respectively. Low levels of inosine were detectable at 50 micrograms/kg following oral administration of PD 141955.
Gilbertsen
R B
RB
Department of Immunopathology, Parke-Davis Pharmaceutical Research, Warner-Lambert Co., Ann Arbor, MI 48105.
Josyula
U
U
Sircar
J C
JC
Dong
M K
MK
Wu
W S
WS
Wilburn
D J
DJ
Conroy
M C
MC
D000818:Animals; D002460:Cell Line; D003848:Deoxyguanine Nucleotides / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006151:Guanosine / Q000097:blood; D006801:Humans; D007288:Inosine / Q000097:blood; D008297:Male; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
D003848:Deoxyguanine Nucleotides; D011743:Pyrimidines; D013876:Thiophenes; C070377:CI 972; D006151:Guanosine; C076778:9-deaza-9-(3-thienylmethyl)guanine; D007288:Inosine; D006147:Guanine; C076777:9-deazaguanine; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase