title: Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
abstract: 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 mm(3)), 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.
authors.affiliation: Topotarget A/S, Symbion, Fruebjergvej 3, Copenhagen DK-2100, Denmark.
authors.forename: Mette K
authors.initials: MK
authors.lastname: Christensen
authors.forename: Kamille D
authors.initials: KD
authors.lastname: Erichsen
authors.forename: Uffe H
authors.initials: UH
authors.lastname: Olesen
authors.forename: Jette
authors.initials: J
authors.lastname: Tjørnelund
authors.forename: Peter
authors.initials: P
authors.lastname: Fristrup
authors.forename: Annemette
authors.initials: A
authors.lastname: Thougaard
authors.forename: Søren Jensby
authors.initials: SJ
authors.lastname: Nielsen
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jensen
authors.forename: Einars
authors.initials: E
authors.lastname: Loza
authors.forename: Ivars
authors.initials: I
authors.lastname: Kalvinsh
authors.forename: Antje
authors.initials: A
authors.lastname: Garten
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.forename: Fredrik
authors.initials: F
authors.lastname: Björkling
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006146:Guanidines / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D006877:Hydroxamic Acids; D054409:Nicotinamide Phosphoribosyltransferase; C004711:dicyandiamido