ANTIPROLIFERATIVE NAPHTHOPYRANS - BIOLOGICAL-ACTIVITY, MECHANISTIC STUDIES AND THERAPEUTIC POTENTIAL

Authors
Citation
Cp. Dell, ANTIPROLIFERATIVE NAPHTHOPYRANS - BIOLOGICAL-ACTIVITY, MECHANISTIC STUDIES AND THERAPEUTIC POTENTIAL, Current medicinal chemistry, 5(3), 1998, pp. 179-194
Citations number
116
Categorie Soggetti
Chemistry Medicinal",Biology,"Pharmacology & Pharmacy
Journal title
ISSN journal
09298673
Volume
5
Issue
3
Year of publication
1998
Pages
179 - 194
Database
ISI
SICI code
0929-8673(1998)5:3<179:AN-BMS>2.0.ZU;2-V
Abstract
This article will firstly briefly review the newer generation of immun osuppressant drugs, focusing mainly on tacrolimus (FK-506). sirolimus (rapamycin), mycophenolate mofetil (RS-61443) and leflunomide (HWA 486 ) and then describe work carried out at the Lilly Research Centre on a nalogues of leflunomide and subsequent diversion into a structurally d istinct series of compounds, the naphthopyrans. A clear structure acti vity relationship exists within this series and selected data from a C oncanavalin A stimulated T-cell proliferation assay are presented to i llustrate this. Although the compounds proved to possess little in viv o activity in our rheumatoid arthritis program, examination of the com pounds in in vitro and in vivo models within the diabetic: complicatio ns group showed the compounds behaved as would be anticipated for inhi bitors of protein kinase C, although this direct mode of action was cl early not correct. Mechanistic investigations revealed that the favour ed compound 290181 blocks phorbol 12',13-dibutyrate-induced binding of transcription factor proteins to the PEA3/TRE sequence of the promote r region of the urokinase plasminogen activator gene. The compounds al so showed antiproliferative effects on vascular smooth muscle cells, a n in vitro activity that translated into in vivo efficacy in a rat mod el of restenosis. Mechanistic studies here demonstrated that 290181 bl ocks proliferation in the G(2)/M phase of the cell cycle by binding di rectly to a novel site on tubulin. Finally the compounds were shown to inhibit the release of neutral proteases from interleukin-1 stimulate d articular chondrocytes, this activity having implications in the deg enerative aspects of osteoarthritis.