title: 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.
authors: Pharmaceutical Sciences Institute, Aston University, Birmingham, United Kingdom.
authors: M F
authors: MF
authors: Stevens
authors: J A
authors: JA
authors: Hickman
authors: S P
authors: SP
authors: Langdon
authors: D
authors: D
authors: Chubb
authors: L
authors: L
authors: Vickers
authors: R
authors: R
authors: Stone
authors: G
authors: G
authors: Baig
authors: C
authors: C
authors: Goddard
authors: N W
authors: NW
authors: Gibson
authors: J A
authors: JA
authors: Slack
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003606:Dacarbazine / Q000627:therapeutic use*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010954:Plasmacytoma / Q000188:drug therapy; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013045:Species Specificity; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D003606:Dacarbazine; D000077204:Temozolomide