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Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
|Title||Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Zheng X, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho Y-C, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Oh A, Wang W, Zak M, Gunzner-Toste J, Zhao G, Yuen P-W, Bair KW|
|Journal||Journal of medicinal chemistry|
|Date Published||2013 Jun 27|
Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).
|Alternate Journal||J. Med. Chem.|