1 Department of Chemistry, Technical University of Denmark2 Organic Chemistry, Department of Chemistry, Technical University of Denmark3 TopoTarget A/S4 Latvian Institute of Organic Synthesis5 University of Leipzig6 Latvian Institute of Organic Synthesis
Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. Using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described and compounds optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives the new analogues exhibit an equally potent anti-proliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed sub-nanomolar anti-proliferative activity towards a series of cancer cell-lines (compound 15: IC50 0.025 nM and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively), and potent anti-tumour in vivo activity in well tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumours (500 mm3) compound 15 reduced the tumour volume to one fifth of the starting volume at a dose of 3 mg/kg administered i.p., bid, day 1-9. Thus, compounds found in this study compared favourably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
Open Journal of Medicinal Chemistry, 2013, Vol 56, Issue 22, p. 9071-9088