Journal article
Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship
Topotarget A/S, Symbion, Fruebjergvej 3, Copenhagen DK-21001
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences2
Experimental Pathology Unit3
Center for Pediatric Research, Hospital for Children and Adolescents4
Department of Chemistry5
Aizkraukles 21, Riga LV-10066
Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure–activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are 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 antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model.
In an A2780 xenograft mouse model with large tumors (500 mm3), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1–9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
Language: | English |
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Publisher: | American Chemical Society |
Year: | 2013 |
Pages: | 9071-9088 |
ISSN: | 15204804 and 00222623 |
Types: | Journal article |
DOI: | 10.1021/jm4009949 |