928649-50-7Relevant articles and documents
Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors
Zheng, Xiaozhang,Baumeister, Timm,Buckmelter, Alexandre J.,Caligiuri, Maureen,Clodfelter, Karl H.,Han, Bingsong,Ho, Yen-Ching,Kley, Nikolai,Lin, Jian,Reynolds, Dominic J.,Sharma, Geeta,Smith, Chase C.,Wang, Zhongguo,Dragovich, Peter S.,Oh, Angela,Wang, Weiru,Zak, Mark,Wang, Yunli,Yuen, Po-Wai,Bair, Kenneth W.
, p. 337 - 343 (2014/01/17)
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 = 2.5 nM, A2780 cell proliferation IC50 = 9.7 nM). 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.
Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
Dragovich, Peter S.,Bair, Kenneth W.,Baumeister, Timm,Ho, Yen-Ching,Liederer, Bianca M.,Liu, Xiongcai,Liu, Yongbo,O'Brien, Thomas,Oeh, Jason,Sampath, Deepak,Skelton, Nicholas,Wang, Leslie,Wang, Weiru,Wu, Hongxing,Xiao, Yang,Yuen, Po-Wai,Zak, Mark,Zhang, Lei,Zheng, Xiaozhang
, p. 4875 - 4885 (2013/09/02)
Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10 nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.
6-ARYLALKYLAMINO- 2,3,4,5-TETRAHYDRO-1H-BENZO[D]AZEPINES AS 5-HT2C RECEPTOR AGONISTS
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Page/Page column 123, (2010/11/26)
The present invention provides 6-substituted 2,3,4,5-tetrahydro-lH- benzo[d]azepines of Formula (I) as selective 5-HT2c receptor agonists for the treatment of 5-HT2c associated disorders including obesity, obsessive/compulsive disorder, depression, and anxiety, where, R6 is -NR10R11, where R10 is substituted phenylalkyl or substituted pyridylalkyl and other substituents are as defined in the specification.
