Abstract
Four novel, disubstituted diaminopteridines have been identified which antagonize the uptake of a folate precursor (para-aminobenzoic acid) by rat-derived Pneumocystis carinii maintained in short-term axenic culture at concentrations ranging from 4.5 to 26 microM. The compounds were at least 10 to 100 times more active than trimethoprim in this assay. None of these entities exhibited toxicity to mammalian cell lines at < 100 microM. The same structures also caused significant inhibition of Toxoplasma gondii tachyzoite replication within Madin-Darby bovine kidney cells at concentrations ranging from 0.1 to 10 microM. Three of the structures (GR92754, AH10639, and AH2504) were at least an order of magnitude more potent than the standard anti-T. gondii agent, pyrimethamine. All three entities were also significantly more potent and selective than pyrimethamine as inhibitors of T. gondii dihydrofolate reductase (DHFR), with 50% inhibitory concentrations within the range of 0.018 to 0.033 microM. One of these compounds, 6,7-dibutyl-2,4-diaminopteridine (GR92754), was also a potent and selective inhibitor of P. carinii DHFR (50% inhibitory concentration, 0.082 microM). GR92754 is the first DHFR inhibitor described that exhibits greater potency, selectivity, and intracellular activity against both organisms than any of the DHFR agents used clinically, namely, trimethoprim, pyrimethamine, and trimetrexate. This information could provide the starting point for examination of the pharmacokinetic and therapeutic potential of GR92754 and related chemical entities with animal models.
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Selected References
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- Allegra C. J., Kovacs J. A., Drake J. C., Swan J. C., Chabner B. A., Masur H. Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent. J Exp Med. 1987 Mar 1;165(3):926–931. doi: 10.1084/jem.165.3.926. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Broughton M. C., Queener S. F. Pneumocystis carinii dihydrofolate reductase used to screen potential antipneumocystis drugs. Antimicrob Agents Chemother. 1991 Jul;35(7):1348–1355. doi: 10.1128/aac.35.7.1348. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chio L. C., Queener S. F. Identification of highly potent and selective inhibitors of Toxoplasma gondii dihydrofolate reductase. Antimicrob Agents Chemother. 1993 Sep;37(9):1914–1923. doi: 10.1128/aac.37.9.1914. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Edman J. C., Edman U., Cao M., Lundgren B., Kovacs J. A., Santi D. V. Isolation and expression of the Pneumocystis carinii dihydrofolate reductase gene. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8625–8629. doi: 10.1073/pnas.86.22.8625. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gangjee A., Vasudevan A., Queener S. F., Kisliuk R. L. 6-substituted 2,4-diamino-5-methylpyrido[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents. J Med Chem. 1995 May 12;38(10):1778–1785. doi: 10.1021/jm00010a022. [DOI] [PubMed] [Google Scholar]
- Hughes W. T., LaFon S. W., Scott J. D., Masur H. Adverse events associated with trimethoprim-sulfamethoxazole and atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia. J Infect Dis. 1995 May;171(5):1295–1301. doi: 10.1093/infdis/171.5.1295. [DOI] [PubMed] [Google Scholar]
- Kovacs J. A., Allegra C. J., Beaver J., Boarman D., Lewis M., Parrillo J. E., Chabner B., Masur H. Characterization of de novo folate synthesis in Pneumocystis carinii and Toxoplasma gondii: potential for screening therapeutic agents. J Infect Dis. 1989 Aug;160(2):312–320. doi: 10.1093/infdis/160.2.312. [DOI] [PubMed] [Google Scholar]
- Kovacs J. A., Allegra C. J., Kennedy S., Swan J. C., Drake J., Parrillo J. E., Chabner B., Masur H. Efficacy of trimetrexate, a potent lipid-soluble antifolate, in the treatment of rodent Pneumocystis carinii pneumonia. Am J Trop Med Hyg. 1988 Nov;39(5):491–496. doi: 10.4269/ajtmh.1988.39.491. [DOI] [PubMed] [Google Scholar]
- Merali S., Zhang Y., Sloan D., Meshnick S. Inhibition of Pneumocystis carinii dihydropteroate synthetase by sulfa drugs. Antimicrob Agents Chemother. 1990 Jun;34(6):1075–1078. doi: 10.1128/aac.34.6.1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Podzamczer D., Salazar A., Jiménez J., Consiglio E., Santín M., Casanova A., Rufí G., Gudiol F. Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Ann Intern Med. 1995 May 15;122(10):755–761. doi: 10.7326/0003-4819-122-10-199505150-00004. [DOI] [PubMed] [Google Scholar]
- Rosowsky A., Hynes J. B., Queener S. F. Structure-activity and structure-selectivity studies on diaminoquinazolines and other inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. Antimicrob Agents Chemother. 1995 Jan;39(1):79–86. doi: 10.1128/aac.39.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosowsky A., Mota C. E., Wright J. E., Queener S. F. 2,4-Diamino-5-chloroquinazoline analogues of trimetrexate and piritrexim: synthesis and antifolate activity. J Med Chem. 1994 Dec 23;37(26):4522–4528. doi: 10.1021/jm00052a011. [DOI] [PubMed] [Google Scholar]
- Schwartz D. E., Rieder J. Pharmacokinetics of sulfamethoxazole plus trimethoprim in man and their distribution in the rat. Chemotherapy. 1970;15(6):337–355. doi: 10.1159/000220701. [DOI] [PubMed] [Google Scholar]
- Walzer P. D., Foy J., Steele P., Kim C. K., White M., Klein R. S., Otter B. A., Allegra C. Activities of antifolate, antiviral, and other drugs in an immunosuppressed rat model of Pneumocystis carinii pneumonia. Antimicrob Agents Chemother. 1992 Sep;36(9):1935–1942. doi: 10.1128/aac.36.9.1935. [DOI] [PMC free article] [PubMed] [Google Scholar]