- Synthesis and Characterization of N-(4-(Piperidin-4-ylsulfonyl) phenyl)5-vinylpyrimidin-2-amine
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Target product N-(4-(piperidin-4-ylsulfonyl)phenyl)5-vinylpyrimidin-2- amine (13) was synthesized using 6-oxopyran-3-carbaldehyde (M1) and 4-hydroxypiperidine (M2) as starting materials by a series of nucleophilic substitution and oxidation. Different aci
- Dong, Jingjing,Feng, Baicheng,Jin, Yan,Lu, Jianqiang,Wang, Tielin
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p. 255 - 258
(2021/08/05)
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- Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility
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Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering c Log D7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.
- Zak, Mark,Liederer, Bianca M.,Sampath, Deepak,Yuen, Po-Wai,Bair, Kenneth W.,Baumeister, Timm,Buckmelter, Alexandre J.,Clodfelter, Karl H.,Cheng, Eric,Crocker, Lisa,Fu, Bang,Han, Bingsong,Li, Guangkun,Ho, Yen-Ching,Lin, Jian,Liu, Xiongcai,Ly, Justin,O'Brien, Thomas,Reynolds, Dominic J.,Skelton, Nicholas,Smith, Chase C.,Tay, Suzanne,Wang, Weiru,Wang, Zhongguo,Xiao, Yang,Zhang, Lei,Zhao, Guiling,Zheng, Xiaozhang,Dragovich, Peter S.
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p. 529 - 541
(2015/03/05)
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- Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
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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.
- 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
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p. 4875 - 4885
(2013/09/02)
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- AMIDO-BENZYL SULFONE AND SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
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Page/Page column 152; 153; 165; 166
(2013/09/12)
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- THIAZOLE INHIBITORS TARGETING RESISTANT AND KINASE MUTATIONS
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A compound is provided, having the general structure (A): wherein A is an aryl or heteroaryl group, Y is a hydrophobic linking moiety, and L is a substitutent. The compound (A) can be used for treatment of various angiogenic-associated or hematologic disorders, such as myeloproliferative disorders in patients who do not respond to kinase-inhibition therapy that comprises administering currently used medications.
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Page/Page column 51-52
(2010/11/27)
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- Phenylsulphonyl derivatives as 5-HT receptor ligands
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A class of phenylsulphonyl derivatives wherein the sulphonyl moiety is also attached to an N-arylalkyl-substituted azetidine, pyrrolidine or piperidine ring are selective antagonists of the human 5-HT2Areceptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including schizophrenia and depression.
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- 4-(Phenylsulfonyl)piperidines: Novel, selective, and bioavailable 5-HT2A receptor antagonists
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On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identifed as high-affinity, selective 5-HT2A receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfon
- Fletcher, Stephen R.,Burkamp, Frank,Blurton, Peter,Cheng, Susan K. F.,Clarkson, Robert,O'Connor, Desmond,Spinks, Daniel,Tudge, Matthew,Van Niel, Monique B.,Patel, Smita,Chapman, Kerry,Marwood, Rose,Shepheard, Sara,Bentley, Graham,Cook, Gina P.,Bristow, Linda J.,Castro, Jose L.,Hutson, Peter H.,MacLeod, Angus M.
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p. 492 - 503
(2007/10/03)
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