Isoxazolylthioamides as potential immunosuppressants a combinatorial chemistry approach.
A library of thioamide derivatives of leflunomide 1a and of its bioactive metabolite 1b has been synthesised on solid phase. Thus, para-substituted phenylacetic acids were coupled to TentaGel and were subsequently reacted with aromatic isothiocyanates. Treatment of the resulting enaminothioamides with hydroxylamine led to their simultaneous cyclisation and cleavage from the resin affording 2-25. Their in vitro profiling demonstrated that the amide-thioamide isologous substitution was detrimental of the biological activity.
Albert
R
R
Novartis Pharma AG, Basel, Switzerland. rainer.albert@pharma.novartis.com
Knecht
H
H
Andersen
E
E
Hungerford
V
V
Schreier
M H
MH
Papageorgiou
C
C
D000818:Animals; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D019811:Hydroxylamine; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D017879:Isothiocyanates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077339:Leflunomide; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010648:Phenylacetates / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D017879:Isothiocyanates; D007555:Isoxazoles; D010648:Phenylacetates; D011994:Recombinant Proteins; D019811:Hydroxylamine; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000077339:Leflunomide