2,4-Diamino-5-benzylpyrimidines and analogs as antibacterial agents. 9. Lipophilic trimethoprim analogs as antigonococcal agents

• Published in: Journal of medicinal chemistry Vol. 31; no. 1; pp. 122 - 129
• Main Authors: Roth, B, Baccanari, D. P, Sigel, C. W, Hubbell, J. P, Eaddy, J, Kao, J. C, Grace, M. E, Rauckman, B. S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-01-1988
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Bacteria - drug effects; Benzyl Compounds - chemical synthesis; Benzyl Compounds - pharmacology; Dogs; Female; Folic Acid Antagonists; Liver - enzymology; Male; Microbial Sensitivity Tests; Neisseria gonorrhoeae; Neisseria gonorrhoeae - drug effects; Neisseria gonorrhoeae - enzymology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Rats; Rats, Inbred Strains; Trimethoprim - analogs & derivatives; Trimethoprim - chemical synthesis; Trimethoprim - pharmacokinetics; Trimethoprim - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00396a018

Lipophilic analogues of trimethoprim (1) bearing 3,5-dialkyl-4-hydroxy substituents in the benzene ring are much more active in vitro against Neisseria gonorrhoeae than is 1. The 3,5-diisopropyl-4-hydroxy derivative (2) was selected as a candidate for clinical evaluation as an antigonococcal agent, and as part of the preliminary evaluation it was submitted to extended pharmacokinetic and metabolism studies in dogs. Although the compound was not extensively conjugated by metabolic enzymes, one of the methyl groups was metabolized to produce a 3-isopropyl-4-hydroxy-5-(alpha-carboxyethyl)benzyl derivative (43), which was rapidly excreted. Related analogues were likewise extensively metabolized.