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Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine.

Abstract
A number of 3-alkyl analogues of the experimental antitumor drug mitozolomide [8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H )-one] have been screened against murine tumors in vivo. Only the compounds with a 3-methyl- or 3-bromoethyl group possessed significant antitumor activity against the TLX5 lymphoma. The 3-methyl analogue, 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045), was investigated further and found to possess good activity, when administered i.p., against the L1210 and P388 leukemias, the M5076 reticulum cell sarcoma, B16 melanoma, and ADJ/PC6A plasmacytoma. The drug was also active when administered p.o. to mice bearing the L1210 leukemia. A daily for 5 days schedule of 100 mg/kg CCRG 81045 produced increases of survival time of treated animals compared to controls of 176 and greater than 235% against the P388 and L1210 leukemias, respectively. In the female C57BL x DBA/2 F1 mouse the 10% lethal dose was 125 mg/kg daily for 5 days. CCRG 81045 was found to undergo mild alkaline hydrolysis and ring fission to form the linear triazene 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide, which is the putative metabolite formed upon metabolic activation of the antitumor drug dacarbazine [5-(3,3-dimethyltriazen-1-yl)imidazole-4-carboxamide]. The half-life of CCRG 81045 at 37 degrees C in 0.2 M phosphate buffer (pH 7.4) was 1.24 h, whereas that of 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide at 25 degrees C was reported to be 8 min (F. H. Shealy and C. A. Krauth, J. Med. Chem., 9:34-37, 1966). The half-life of CCRG 81045 in human plasma in vitro at 37 degrees C was 0.42 h. Pharmacokinetic experiments conducted in BALB/c mice produced plasma profiles of CCRG 81045, administered i.p. or p.o., which showed a rapid absorption phase, elimination half-lives of 1.13 h (i.p.) and 1.29 h (p.o.), and a bioavailability of 0.98.
AuthorsM F Stevens, J A Hickman, S P Langdon, D Chubb, L Vickers, R Stone, G Baig, C Goddard, N W Gibson, J A Slack
JournalCancer research (Cancer Res) Vol. 47 Issue 22 Pg. 5846-52 (Nov 15 1987) ISSN: 0008-5472 [Print] United States
PMID3664486 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Imidazoles
  • Dacarbazine
  • Temozolomide
Topics
  • Animals
  • Antineoplastic Agents (therapeutic use)
  • Dacarbazine (therapeutic use)
  • Imidazoles (pharmacokinetics, therapeutic use, toxicity)
  • Lung Neoplasms (drug therapy)
  • Male
  • Melanoma, Experimental (drug therapy)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred CBA
  • Mice, Inbred DBA
  • Mice, Inbred Strains
  • Neoplasms, Experimental (drug therapy)
  • Plasmacytoma (drug therapy)
  • Sarcoma, Experimental (drug therapy)
  • Species Specificity
  • Temozolomide

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