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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Zheng X,Baumeister T,Buckmelter AJ,Caligiuri M,Clodfelter KH,Han B,Ho YC,Kley N,Lin J,Reynolds DJ,Sharma G,Smith CC,Wang Z,Dragovich PS,Oh A,Wang W,Zak M,Wang Y,Yuen PW,Bair KWdoi
10.1016/j.bmcl.2013.11.006subject
Has Abstractpub_date
2014-01-01 00:00:00pages
337-43issue
1eissn
0960-894Xissn
1464-3405pii
S0960-894X(13)01285-7journal_volume
24pub_type
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