Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship

Abstract

Abstract.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: IC 50 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 mm 3 ) 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.

Physiological and pathophysiological roles of NAMPT and NAD metabolism

“…Several research groups have characterized the structural and enzymological features of mammalian NAMPT. [24][25][26][27][28][29][30][31] Structural and mutagenesis studies have shown that mutations in NAMPT that impair dimerization attenuate enzymatic activity; 26 furthermore, Asp219 is important in defining the substrate specificity of NAMPT, 29 which does not include nicotinic acid. 14,32 Autophosphorylation of NAMPT (by use of ATP) at His247 24,26 creates a reaction intermediate that is hydrolysed during each catalytic cycle, which increases the affinity of NAMPT for NAM and its enzymatic activity up to 1,000-fold.…”

“…22 Targeting NAMPT activity, thus, represents a novel therapeutic strategy for treating human cancers. For example, the specific NAMPT inhibitor FK866 has been evaluated in a broad variety of tumours, including solid tumours and leukemias, 153,167,168 both in vitro and in nude-mouse xenografts, 31,167,[169][170][171] in which FK866 was able to reduce or attenuate tumour growth. NAMPT inhibition also attenuates glycolysis in conjunction with reduced NAD levels, which leads to blockade of the pentose phosphate pathway, serine biosynthesis and the tricarboxylic acid cycle.…”

FK866-induced NAMPT inhibition activates AMPK and downregulates mTOR signaling in hepatocarcinoma cells

“…The specific NAMPT inhibitor FK866 is a competitive inhibitor that was selected by an anticancer screening system differentiating acute cytotoxicity from growth inhibition [12;13]. FK866 has been evaluated in a broad variety of M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT tumors, including solid tumors and leukemia [14][15][16] in vitro and in nude mouse xenografts [17][18][19], where FK866 was able to reduce or attenuate tumor growth.…”

Deoxyalkoxyamination of Alcohols for the Synthesis of N‐Alkoxy‐N‐alkylbenzenesulfonamides

“…However, the preparation of O ‐alkyl hydroxylamine hydrochlorides with various substituents was not convenient. Another protocol for the synthesis of this compound is alkylation with alcohol under Mitsunobu conditions, or with alkyl bromide in the presence of K 2 CO 3 in DMSO (Scheme b) . However, this protocol involved two steps, namely sulfonylation and alkylation.…”