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

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 mol...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1986-06, Vol.29 (6), p.1099-1113
Main Authors: Blythin, David J, Kaminski, James J, Domalski, Martin S, Spitler, James, Solomon, Daniel M, Conn, David J, Wong, Shing Chun, Verbiar, Laura Lehman, Bober, Loretta A
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - chemical synthesis
Anti-Inflammatory Agents - metabolism
Anti-Inflammatory Agents - pharmacology
Arthritis - drug therapy
Biological Availability
Chemistry
Condensed matter: structure, mechanical and thermal properties
Cyclooxygenase Inhibitors
Exact sciences and technology
Gastrointestinal Diseases - chemically induced
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
Male
Organic chemistry
Organic compounds
Physics
Preparations and properties
Purines - chemical synthesis
Purines - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
Rats
Rats, Inbred Strains
Structure of solids and liquids
crystallography
Structure of specific crystalline solids
Structure-Activity Relationship
Ulcer - chemically induced
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00156a032