27420-41-3Relevant academic research and scientific papers
Substituted pyridopyrimidinones, 1: Convenient PTC alkylation and halogenation of 2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one
Abass, Mohamed,Mayas, Aisha S.
, p. 19 - 27 (2007)
Alkylation of 2-hydroxy-4H-pyrido[1,2-a]-pyrimidin-4-one (1) was investigated under solid-liquid phase transfer catalysis conditions (PTC), using tetrabutylammonium bromide and potassium carbonate. The reaction with alkyl halides led to the formation of various 2-alkoxy products, in fair yields. Reaction of compound 1 with epichlorohydrin and chloroacetonitrile, under the same PTC conditions, afforded novel O1,O3-disubstituted glycerol and oxazolopyridopyrimidone betaine derivatives, respectively. Some 3-halo-, 3,3-dihalo, and/or 2,3-dihalopyrido[1,2-a]pyrimidines were also prepared using different halogenating agents at different reaction conditions.
Structure-activity relationship of spop inhibitors against kidney cancer
Dong, Ze,Wang, Zhen,Guo, Zhong-Qiang,Gong, Shouzhe,Zhang, Tao,Liu, Jiang,Luo, Cheng,Jiang, Hualiang,Yang, Cai-Guang
, p. 4849 - 4866 (2020/06/08)
Speckle-type POZ protein (SPOP) is overexpressed in the nucleus and misallocated in the cytoplasm in almost all the clear-cell renal cell carcinomas (ccRCCs), which leads to kidney tumorigenesis. Previously, we elucidated that the oncogenic SPOP-signaling pathway in ccRCC could be suppressed by 6b that inhibits SPOP-mediated protein interactions. Herein, we have established a structure-activity relationship for 6b analogues as SPOP inhibitors. Compound 6lc suppresses the viability and inhibits the colony formation of ccRCC cell lines driven by cytoplasmic SPOP, superior to 6b. Compound 6lc binds to the SPOP protein in vitro and disrupts SPOP binding to phosphatase-and-tensin homologue (PTEN) in HEK293T cells, which causes the observable phenomena: a decline in the ubiquitination of PTEN, elevated levels of both PTEN and dual-specificity phosphatase 7, and decreased levels of phosphorylated AKT and ERK when ccRCC cell lines are exposed to 6lc in a dose-response manner. Taken together, compound 6lc is a potent candidate against kidney tumorigenesis.
Discovery and Characterization of (R)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates
Stepan, Antonia F.,Claffey, Michelle M.,Reese, Matthew R.,Balan, Gayatri,Barreiro, Gabriela,Barricklow, Jason,Bohanon, Michael J.,Boscoe, Brian P.,Cappon, Gregg D.,Chenard, Lois K.,Cianfrogna, Julie,Chen, Laigao,Coffman, Karen J.,Drozda, Susan E.,Dunetz, Joshua R.,Ghosh, Somraj,Hou, Xinjun,Houle, Christopher,Karki, Kapil,Lazzaro, John T.,Mancuso, Jessica Y.,Marcek, John M.,Miller, Emily L.,Moen, Mark A.,O'Neil, Steven,Sakurada, Isao,Skaddan, Marc,Parikh, Vinod,Smith, Deborah L.,Trapa, Patrick,Tuttle, Jamison B.,Verhoest, Patrick R.,Walker, Daniel P.,Won, Annie,Wright, Ann S.,Whritenour, Jessica,Zasadny, Kenneth,Zaleska, Margaret M.,Zhang, Lei,Shaffer, Christopher L.
, p. 7764 - 7780 (2017/10/10)
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
Characterization and structure-activity relationship study of iminodipyridinopyrimidines as novel hepatitis C virus inhibitor
Park, Dong-Sik,Jo, Eunji,Choi, Jihyun,Lee, MyungEun,Kim, Soohyun,Kim, Hee-Young,Nam, Jiyon,Ahn, Sujin,Hwang, Jong Yeon,Windisch, Marc Peter
, p. 65 - 73 (2017/09/20)
Upon high-throughput screening of synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified an iminodipyridinopyrimidine (IDPP) scaffold. IDPP did not inhibit HCV replication, but exhibited very potent inhibitory activity on early and late steps of HCV life cycle. Applying an intensive structure-activity relationship (SAR) study, a promising IDPP Lead compound (12c) with excellent potency (EC50 = 10 nM), high safety margin (SI > 2000), and an acceptable stability in human and rat liver microsomes (t1/2 >60 min) was identified. Overall, our results suggest that the IDPP scaffold could be used for the development of novel HCV interventions.
QUINAZOLINONE COMPOUNDS AND DERIVATIVES THEREOF
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Paragraph 0224; 0225, (2014/03/25)
Compounds of Formula I are useful inhibitors of tankyrase. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.
On the synthesis of pyridinylthiobarbituric acids
Deady, Leslie W.,Ganame, Daniel,Hughes, Andrew B.,Quazi, Nurul H.,Zanatta, Shannon D.
, p. 287 - 289 (2007/10/03)
The reaction of N-(pyridin-3-yl) and -4-yl thiourea derivatives with malonyl dichloride in trifluoroacetic acid is shown to be an efficient synthesis of the corresponding thiobarbituric acids. The pyridin-2-yl analogue cleaved and produced, instead, 2-hyd
