Antiproliferative naphthopyrans: biological activity, mechanistic studies and therapeutic potential.
This article will firstly briefly review the newer generation of immunosuppressant 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 analogues of leflunomide and subsequent diversion into a structurally distinct series of compounds, the naphthopyrans. A clear structure activity relationship exists within this series and selected data from a Concanavalin A stimulated T-cell proliferation assay are presented to illustrate this. Although the compounds proved to possess little in vivo activity in our rheumatoid arthritis program, examination of the compounds in in vitro and in vivo models within the diabetic complications group showed the compounds behaved as would be anticipated for inhibitors of protein kinase C, although this direct mode of action was clearly not correct. Mechanistic investigations revealed that the favoured compound 290181 blocks phorbol 12,13-dibutyrate-induced binding of transcription factor proteins to the PEA3/TRE sequence of the promoter region of the urokinase plasminogen activator gene. The compounds also showed antiproliferative effects on vascular smooth muscle cells, an in vitro activity that translated into in vivo efficacy in a rat model of restenosis. Mechanistic studies here demonstrated that 290181 blocks proliferation in the G2/M phase of the cell cycle by binding directly to a novel site on tubulin. Finally the compounds were shown to inhibit the release of neutral proteases from interleukin-1 stimulated articular chondrocytes, this activity having implications in the degenerative aspects of osteoarthritis.
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Eli Lilly and Company, Lilly Research Centre, Erl Wood Manor, Windlesham, GU20 6PH, UK.
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010003:Osteoarthritis / Q000188:drug therapy; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; C094200:LY 290181; D009281:Naphthalenes; D011714:Pyrans