| Literature DB >> 24279990 |
Xiaozhang Zheng1, Timm Baumeister2, Alexandre J Buckmelter2, Maureen Caligiuri2, Karl H Clodfelter2, Bingsong Han2, Yen-Ching Ho2, Nikolai Kley2, Jian Lin2, Dominic J Reynolds2, Geeta Sharma2, Chase C Smith2, Zhongguo Wang2, Peter S Dragovich3, Angela Oh3, Weiru Wang3, Mark Zak3, Yunli Wang4, Po-Wai Yuen4, Kenneth W Bair2.
Abstract
A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.Entities:
Keywords: Nampt; Nicotinamide phosphoribosyltransferase; X-ray crystal structure; cyanoguanidine
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Year: 2013 PMID： 24279990 DOI： 10.1016/j.bmcl.2013.11.006
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823