2. Academic Validation
  3. Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors

Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors

  • J Med Chem. 2013 Jun 27;56(12):4921-37. doi: 10.1021/jm400186h.
Xiaozhang Zheng 1,  Paul Bauer,  Timm Baumeister,  Alexandre J Buckmelter,  Maureen Caligiuri,  Karl H Clodfelter,  Bingsong Han,  Yen-Ching Ho,  Nikolai Kley,  Jian Lin,  Dominic J Reynolds,  Geeta Sharma,  Chase C Smith,  Zhongguo Wang,  Peter S Dragovich,  Angela Oh,  Weiru Wang,  Mark Zak,  Janet Gunzner-Toste,  Guiling Zhao,  Po-wai Yuen,  Kenneth W Bair
Affiliations

Affiliation

  • 1 Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, Massachusetts 02472, USA. xzheng@formatherapeutics.com
PMID: 23617784 DOI: 10.1021/jm400186h
Abstract

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).

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