Biochemical and pharmacological properties of CI-972, a novel 9-deazaguanine analog purine nucleoside phosphorylase (PNP) inhibitor.
CI-972 (2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3, 2-d]pyrimidin-4-one monohydrochloride, monohydrate) is a novel inhibitor of PNP (Ki = 0.83 microM) under development as a T cell-selective immunosuppressive agent. CI-972 inhibited proliferation (3H-thymidine uptake) of human MOLT-4 (T cell) but not MGL-8 (B cell) lymphoblasts with respective IC50s of 3.0 and greater than 50 microM when tested with 10 microM 2'-deoxyguanosine. Without addition of exogenous 2'-deoxyguanosine, CI-972 was not inhibitory to any human T or B lymphoblastoid cell line tested. 2'-Deoxycytidine (10 microM), but not hypoxanthine or adenine, restored MOLT-4 cell growth. Inhibition of 3H-thymidine uptake in MOLT-4 cells correlated with accumulation of dGTP, while alterations in guanine nucleotides were not observed. 2'-Deoxycytidine (10 microM) also blocked dGTP accumulation in MOLT-4 cells. CI-972 showed activity in vivo over a broad dose range: At 5-150 mg/kg p.o., CI-972 produced dose-dependent elevation of plasma inosine one hr after administration to rats (mean maximum of 2.62 vs. 0.06 microM in controls). Guanosine was also significantly elevated in a concentration-dependent manner, although the effect was not as impressive. Plasma nucleosides remained statistically-significantly elevated for up to four hr following a single oral dose of CI-972.
Gilbertsen
R B
RB
Department of Immunopathology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Dong
M K
MK
Wilburn
D J
DJ
Kossarek
L M
LM
Sircar
J C
JC
Kostlan
C R
CR
Conroy
M C
MC
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D009705:Nucleosides / Q000097:blood*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013876:Thiophenes / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D003848:Deoxyguanine Nucleotides; D009705:Nucleosides; D011743:Pyrimidines; D013876:Thiophenes; C070377:CI 972; D006160:Guanosine Triphosphate; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase; D013936:Thymidine