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.