- A practical chromatography-free synthesis of a 5,6-dihydroimidazolo[1,5-f]pteridine derivative as a polo-like kinase-1 inhibitor
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A practical chromatography-free synthesis of a potent polo-like kinase-1 inhibitor possessing a unique 5,6-dihydroimidazolo[1,5-f]pteridine structure has been developed. We showed that key cyanoimidazole ring formation could be conducted at benign temperature and obtained a chiral 5,6-dihydroimidazolo[1,5-f]pteridine derivative in good yield without epimerization. An aniline derivative containing a trans 1,4-cyclohexyl diamine structure was prepared by a synthesis that makes use of defined stereocenters of commercially available trans-cyclohexane-1,4-diamine via selective piperazine ring formation from a primary diamine. A coupling reaction of the 3-chloro-5,6-dihydroimidazolo[1,5-f]pteridine derivative and the aniline derivative in the endgame was closely investigated, and good yields were achieved both by palladium-catalyzed amination and acid-promoted coupling under benign reaction conditions. As a result of these investigations, the polo-like kinase-1 inhibitor was successfully obtained in a practical way without concern for generation/separation of stereoisomers.
- Ishimoto, Kazuhisa,Nakaoka, Keiichiro,Yabe, Osamu,Nishiguchi, Atsuko,Ikemoto, Tomomi
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p. 5779 - 5790
(2018/08/25)
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- Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors
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The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase-bromodomain inhibitor (BRD4-BD1 IC50 = 28 nM, PLK1 IC50 = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC50 = 2579 nM, PLK1 IC50 = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.
- Liu, Shuai,Yosief, Hailemichael O.,Dai, Lingling,Huang, He,Dhawan, Gagan,Zhang, Xiaofeng,Muthengi, Alex M.,Roberts, Justin,Buckley, Dennis L.,Perry, Jennifer A.,Wu, Lei,Bradner, James E.,Qi, Jun,Zhang, Wei
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p. 7785 - 7795
(2018/09/13)
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- Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors
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Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
- Kiryanov, Andre,Natala, Srinivasa,Jones, Benjamin,McBride, Christopher,Feher, Victoria,Lam, Betty,Liu, Yan,Honda, Kouhei,Uchiyama, Noriko,Kawamoto, Tomohiro,Hikichi, Yuichi,Zhang, Lilly,Hosfield, David,Skene, Robert,Zou, Hua,Stafford, Jeffrey,Cao, Xiaodong,Ichikawa, Takashi
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p. 1311 - 1315
(2017/06/21)
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- Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors
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Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
- Bowers, Simeon,Truong, Anh P.,Ye, Michael,Aubele, Danielle L.,Sealy, Jennifer M.,Neitz, R. Jeffrey,Hom, Roy K.,Chan, Wayman,Dappen, Michael S.,Galemmo Jr., Robert A.,Konradi, Andrei W.,Sham, Hing L.,Zhu, Yong L.,Beroza, Paul,Tonn, George,Zhang, Heather,Hoffman, Jennifer,Motter, Ruth,Fauss, Donald,Tanaka, Pearl,Bova, Michael P.,Ren, Zhao,Tam, Danny,Ruslim, Lany,Baker, Jeanne,Pandya, Deepal,Diep, Linnea,Fitzgerald, Kent,Artis, Dean R.,Anderson, John P.,Bergeron, Marcelle
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p. 2743 - 2749
(2013/07/19)
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- DIHYDROPTERIDINONE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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Dihydroperidinone derivatives, preparation process and pharmaceutical use thereof are disclosed. Specially, new dihydroperidinone derivatives represented by general formula (I), wherein each substituent of the general formula (I) is defined as in the description, their preparation process, pharmaceutical compositions comprising said derivatives and their use as therapeutical agents, especially as Plk kinase inhibitors are disclosed.
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Page/Page column 57
(2012/08/08)
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- DIHYDROPTERIDINONE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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Dihydroperidinone derivatives, preparation process and pharmaceutical use thereof are disclosed. Specially, new dihydroperidinone derivatives represented by general formula (I), wherein each substituent of the general formula (I) is defined as in the description, their preparation process, pharmaceutical compositions comprising said derivatives and their use as therapeutical agents, especially as Plk kinase inhibitors are disclosed.
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Page/Page column 59
(2012/07/28)
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- CRYSTALLINE FORM OF A DIHYDROPTERIDIONE DERIVATIVE
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The present invention relates to a crystalline form a dihydropteridione derivative, namely a crystalline form of the free base N- [trans-4- [4- (cyclopropylmethyl) - 1-piperazinyl] cyclohexyl] -4- [[(7R) -7-ethyl-5, 6. 7, 8 - tetrahydro - 5 -methyl - 8 -
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Page/Page column 13-14
(2009/04/25)
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- TRIHYDROCHLORIDE FORMS OF A DIHYDROPTERIDINONE DERIVATIVE AND PROCESSES FOR PREPARATION
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The present invention relates to a specific salt of a dihydropteridione derivative, namely the trihydrochloride salt of the compound N-[trans-4-[4-(cyclopropylmethyl)-1- piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl
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Page/Page column 13
(2008/06/13)
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- Process for the manufacture of fused piperazin-2-one derivatives
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Disclsoed are processes for the preparation of fused piperazin-2-one derivatives of general formula (I) wherein the groups R1 to R5, A1 and A2 have the meanings given in the claims and in the description, particularly the preparation of 7,8-dihydro-5H-pteridin-6-one derivatives and intermediates thereof.
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Page/Page column 5
(2008/06/13)
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