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Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.

Publication ,  Journal Article
Blythin, DJ; Kaminski, JJ; Domalski, MS; Spitler, J; Solomon, DM; Conn, DJ; Wong, SC; Verbiar, LL; Bober, LA; Chiu, PJ
Published in: Journal of medicinal chemistry
June 1986

A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.

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Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

June 1986

Volume

29

Issue

6

Start / End Page

1099 / 1113

Related Subject Headings

  • Ulcer
  • Structure-Activity Relationship
  • Rats, Inbred Strains
  • Rats
  • Pyrimidines
  • Purines
  • Medicinal & Biomolecular Chemistry
  • Male
  • Gastrointestinal Diseases
  • Cyclooxygenase Inhibitors
 

Citation

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Blythin, D. J., Kaminski, J. J., Domalski, M. S., Spitler, J., Solomon, D. M., Conn, D. J., … Chiu, P. J. (1986). Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents. Journal of Medicinal Chemistry, 29(6), 1099–1113. https://doi.org/10.1021/jm00156a032
Blythin, D. J., J. J. Kaminski, M. S. Domalski, J. Spitler, D. M. Solomon, D. J. Conn, S. C. Wong, L. L. Verbiar, L. A. Bober, and P. J. Chiu. “Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.Journal of Medicinal Chemistry 29, no. 6 (June 1986): 1099–1113. https://doi.org/10.1021/jm00156a032.
Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, et al. Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents. Journal of medicinal chemistry. 1986 Jun;29(6):1099–113.
Blythin, D. J., et al. “Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.Journal of Medicinal Chemistry, vol. 29, no. 6, June 1986, pp. 1099–113. Epmc, doi:10.1021/jm00156a032.
Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, Wong SC, Verbiar LL, Bober LA, Chiu PJ. Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents. Journal of medicinal chemistry. 1986 Jun;29(6):1099–1113.
Journal cover image

Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

June 1986

Volume

29

Issue

6

Start / End Page

1099 / 1113

Related Subject Headings

  • Ulcer
  • Structure-Activity Relationship
  • Rats, Inbred Strains
  • Rats
  • Pyrimidines
  • Purines
  • Medicinal & Biomolecular Chemistry
  • Male
  • Gastrointestinal Diseases
  • Cyclooxygenase Inhibitors