71406-74-1Relevant academic research and scientific papers
4-ureido pyrimidine compound and application thereof
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Paragraph 0053-0056, (2021/02/20)
The invention relates to a substituted 4-ureido pyrimidine compound and application thereof, and further relates to a pharmaceutical composition containing the substituted 4-ureido pyrimidine compoundand application thereof. The substituted 4-ureido pyrimidine compound or the pharmaceutical composition can be used for inhibiting IDH2. The invention provides a compound shown as a formula I, and astereoisomer, a tautomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof. The compound has good IDH2 inhibitory activity and has good clinical potential application value.
Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors
Barbosa Da Silva, Elany,Rocha, Débora A.,Fortes, Isadora S.,Yang, Wenqian,Monti, Ludovica,Siqueira-Neto, Jair L.,Caffrey, Conor R.,McKerrow, James,Andrade, Saulo F.,Ferreira, Rafaela S.
, p. 13054 - 13071 (2021/09/13)
The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described N4-benzyl-N2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (Ki = 1.4 μM). Here, we describe the synthesis and biological evaluation of 22 analogs of 1a, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations. During the optimization of 1a, structure-based design and prediction of physicochemical properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.
OLEFIN POLYMERIZATION CATALYST SYSTEMS AND METHODS OF USE THEREOF
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Paragraph 0137-0138, (2020/12/19)
An olefin polymerization catalyst system includes a procatalyst component chosen from metal-ligand complexes of Formula (I): In Formula (I), each X is independently a monodentate or polydentate ligand that is neutral, monoanionic, or dianionic; the metal-ligand complex of Formula (I) is overall neutral; each Y1-Y4 and Y7-Y10 independently is selected from C or N such that six membered diaza (N2) or triaza (N3) rings are formed; wherein each R1 and R10 independently are chosen from (C1-C40) hydrocarbyl, substituted (C1-C40) hydrocarbyl, (C1-C40) heterohydrocarbyl, and substituted (C1-C40) heterohydrocarbyl or is absent; each R2, R3, R4, R7, R8, and R9 is chosen from hydrogen; (C1-C40) hydrocarbyl; substituted (C1-C40) hydrocarbyl; (C1-C40) heterohydrocarbyl; substituted (C1-C40) heterohydrocarbyl; halogen, nitro (NO2) or is absent; each R5 and R6 independently is chosen from (C1-C40) hydrocarbyl, substituted (C1-C40) hydrocarbyl, (C1-C40) heterohydrocarbyl, and substituted (C1-C40) heterohydrocarbyl.
Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer
Wang, Xueyuan,Bai, Enhe,Zhou, Hui,Sha, Sijia,Miao, Hang,Qin, Yanru,Liu, Zhaogang,Wang, Jia,Zhang, Haoyang,Lei, Meng,Liu, Jia,Hai, Ou,Zhu, Yongqiang
, p. 533 - 544 (2019/01/04)
Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new molecule entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized. After enzymatic evaluations, structure-activity relationships (SAR) were discussed in detailed. Among the screened compounds, derivative 35 showed excellent enzymatic inhibitory activity (IC50, 36 nM). The cellular inhibition results showed that compound 35 had good antiproliferative activity against the non-small cell lung cancer A549 cells (IC50, 1.61 μM). Liver microsome stability showed that the half-life of compound 35 in human liver microsome was 42.3 min, which was more stable than the control CB-5083 (25.8 min). The in vivo pharmacokinetic results showed that the elimination phase half-lives of compound 35 were 4.57 h for ig and 3.64 h for iv, respectively and the oral bioavailability was only 4.5%. These results indicated that compound 35 could be effective for intravenous treatment of non-small cell lung cancer.
Design, synthesis and biological evaluation of pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors
Sun, Wuji,Hu, Shengquan,Fang, Shubiao,Yan, Hong
, p. 393 - 405 (2018/04/23)
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has already become an attractive approach for cancer therapy. In this study, a novel pyrimidine-based derivative 7j was designed as lead compound, and three series of potent VEGFR-2 inhibitors were synthesized and biologically evaluated against A549 and HepG2 cell lines. Compounds 7d, 9s and 13n exhibited superior inhibitory activities against A549 cell with IC50 ranged from 9.19 to 13.17 μM and HepG2 cell with IC50 ranged from 11.94 to 18.21 μM compared to those of Pazopanib (IC50 = 21.18 and 36.66 μM). In addition, molecular docking study was performed to investigate the binding capacity and binding mode between target compounds and VEGFR-2.
Synthesis and in vitro biological evaluation of new pyrimidines as glucagon-like peptide-1 receptor agonists
AlNeyadi, Shaikha S.,Adem, Abdu,Amer, Naheed,Salem, Alaa A.,Abdou, Ibrahim M.
supporting information, p. 5071 - 5075 (2017/10/11)
The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small-molecule GLP-1 receptor agonists. In this study, two series of new pyrimidine derivatives were designed and synthesized using an efficient route, and were evaluated in terms of GLP-1 receptor agonist activity. In the first series, novel pyrimidines substituted at positions 2 and 4 with groups varying in size and electronic properties were synthesized in a good yield (78–90%). In the second series, the designed pyrimidine templates included both urea and Schiff base linkers, and these compounds were successfully produced with yields of 77–84%. In vitro experiments with cultured cells showed that compounds 3a and 10a (10?15–10?9 M) significantly increased insulin secretion compared to that of the control cells in both the absence and presence of 2.8 mM glucose; compound 8b only demonstrated significance in the absence of glucose. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1 receptor agonists that can be administered orally.
Design, synthesis and structure-activity relationship studies of a focused library of pyrimidine moiety with anti-proliferative and anti-metastasis activities in triple negative breast cancer
Yao, Dahong,Zhou, Yuxin,Zhu, Lingjuan,Ouyang, Liang,Zhang, Jin,Jiang, Yingnan,Zhao, Yuqian,Sun, Dejuan,Yang, Shilin,Yu, Yang,Wang, Jinhui
, p. 155 - 171 (2017/09/20)
Triple-negative breast cancer (TNBC) is a clinical conundrum with distinct clinical and pathologic features, which is characterized by high aggression, poor prognosis, and lack of targeted therapies. In this study, based on the structural features of type II kinase inhibitors, we designed and synthesized a focused library of 41 pyrimidine derivatives possessing potent anti-proliferation activity, Y29 showed the most potent activity against MDA-MB-231 cells. Subsequently, we carried out target prediction, homology modeling, molecular docking, dynamics simulation and determination of enzymatic activity. The results suggested that PDGFR-β was its potential target. In vitro experiments revealed that Y29 attenuated metastasis by PDGFR-β inhibition-induced autophagy and could enhance autophagy-related cell death through AKT-MAPK feedback loop in MDA-MB-231 cells.
Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases
Farmer, Luc J.,Ledeboer, Mark W.,Hoock, Thomas,Arnost, Michael J.,Bethiel, Randy S.,Bennani, Youssef L.,Black, James J.,Brummel, Christopher L.,Chakilam, Ananthsrinivas,Dorsch, Warren A.,Fan, Bin,Cochran, John E.,Halas, Summer,Harrington, Edmund M.,Hogan, James K.,Howe, David,Huang, Hui,Jacobs, Dylan H.,Laitinen, Leena M.,Liao, Shengkai,Mahajan, Sudipta,Marone, Valerie,Martinez-Botella, Gabriel,McCarthy, Pamela,Messersmith, David,Namchuk, Mark,Oh, Luke,Penney, Marina S.,Pierce, Albert C.,Raybuck, Scott A.,Rugg, Arthur,Salituro, Francesco G.,Saxena, Kumkum,Shannon, Dean,Shlyakter, Dina,Swenson, Lora,Tian, Shi-Kai,Town, Christopher,Wang, Jian,Wang, Tiansheng,Wannamaker, M. Woods,Winquist, Raymond J.,Zuccola, Harmon J.
, p. 7195 - 7216 (2015/10/05)
While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.
One-pot synthesis and antiproliferative activity of novel 2,4-diaminopyrimidine derivatives bearing piperidine and piperazine moieties
Ma, Wei-Feng,Yang, Hai-Kui,Hu, Meng-Jin,Li, Qian,Ma, Tian-Zhu,Zhou, Zhong-Zhen,Liu, Rui-Yuan,You, Wen-Wei,Zhao, Pei-Liang
, p. 127 - 134 (2014/07/22)
A series of novel 2,4-diaminopyrimidines containing piperidine and piperazine moieties were synthesized via an efficient one-pot methodology. The bioassay tests demonstrated that compounds 27 and 28 displayed much stronger antitumor activities against four human cancer cell lines (HepG2, A549, MDA-MB-231 and MCF-7) than positive control fluorouracil. Particularly, compound 28 showed a two-fold improvement compared to fluorouracil in inhibiting MDA-MB-231 and A549 cell proliferation with IC50 values of 7.46 and 12.78 μM, respectively. Further flow-activated cell sorting analysis revealed that the most promising compound 28 displayed a significant effect on G 2/M cell-cycle arrest in a dose-dependent manner in MDA-MB-231 cells.
ARYL AMINE SUBSTITUTED PYRIMIDINE AND QUINAZOLINE AND THEIR USE AS ANTICANER DRUGS
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Paragraph 0040; 0042; 0046, (2014/04/03)
A series of mono- and di-substituted quinazoline and pyrimidine derivatives based on the skeleton of erlotinib (an EGFR inhibitor) were synthesized and their bioactivities against hepatocellular carcinoma and human lung adenocarcinoma were evaluated.
