Pyrimidines

Sanchez-Arias, Juan A.; Rabal, Obdulia; Cuadrado-Tejedor, Mar; de Miguel, Irene; Perez-Gonzalez, Marta; Ugarte, Ana; Saez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen published the artcile< Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer's Disease>, Computed Properties of 89793-12-4, the main research area is histone deacetylase phosphodiesterase 5 inhibitor preparation Alzheimer treatment; Alzheimer’s disease; HDACs; PDE5; dual inhibitor; tadalafil; vardenafil.

A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer’s disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead mol. CM-414 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, the authors have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead mol. bearing a different chemotype for in vivo testing.

ACS Chemical Neuroscience published new progress about Alzheimer disease. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Computed Properties of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Zhao, Chao; Choi, You Hee; Khadka, Daulat Bikram; Jin, Yifeng; Lee, Kwang-Youl; Cho, Won-Jea published the artcile< Design and synthesis of novel androgen receptor antagonists via molecular modeling>, SDS of cas: 89793-12-4, the main research area is androgen receptor antagonist preparation cancer; AR antagonist; Bioisostere; Molecular modeling; Nicotinamide; Pyrazinamide; Pyrimidinamide.

Several androgen receptor (AR) antagonists are clin. prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds, 1e exhibited the strongest inhibitory effect on LNCaP cell growth (IC50 = 0.35 μM) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biol. results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied mol. modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chem. modifications.

Bioorganic & Medicinal Chemistry published new progress about Androgen receptor antagonists. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, SDS of cas: 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Chen, Junwei; Cao, Xin; An, Quanlin; Zhang, Yao; Li, Ke; Yao, Wenting; Shi, Fuchun; Pan, Yanfang; Jia, Qiong; Zhou, Wenwen; Yang, Fang; Wei, Fuxiang; Wang, Ning; Yu, Biao published the artcile< Inhibition of cancer stem cell like cells by a synthetic retinoid>, Quality Control of 89793-12-4, the main research area is cancer stem cell synthetic retinoid WYC209 anticancer.

Developing novel drugs that can abrogate the growth and metastasis of malignant tumors is a major challenge for cancer researchers. Here we describe a novel synthetic retinoid, namely WYC-209, which inhibits proliferation of malignant murine melanoma tumor-repopulating cells (TRCs), known to resist conventional drug treatment, with an IC50 of 0.19 μM in a dose-dependent manner. WYC-209 also inhibits proliferation of TRCs of human melanoma, lung cancer, ovarian cancer, and breast cancer in culture. Interestingly, the treated TRCs fail to resume growth even after the drug washout. Importantly, the mol. abrogates 87.5% of lung metastases of melanoma TRCs in immune-competent wild-type C57BL/6 mice at 0.22 mg kg-1 without showing apparent toxicity. Pretreating the melanoma TRCs with retinoic acid receptor (RAR) antagonists or with RAR siRNAs blocks or reduces the inhibitory effect of the mol., suggesting that the target of the mol. is RAR. WYC-209 induces TRC apoptosis and pretreating the TRCs with caspase 3 inhibitor or depleting caspase 3 with siRNAs substantially rescues growth of TRCs from WYC-209 inhibition, suggesting that WYC-209 induces TRCs apoptosis primarily via the caspase 3 pathway. Our findings demonstrate the promise of the new retinoid WYC-209 in treating malignant melanoma tumors with high efficacy and little toxicity.

Nature Communications published new progress about Antiproliferative agents. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Quality Control of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Heffron, Timothy P.; Wei, Bin Qing; Olivero, Alan; Staben, Steven T.; Tsui, Vickie; Do, Steven; Dotson, Jennafer; Folkes, Adrian J.; Goldsmith, Paul; Goldsmith, Richard; Gunzner, Janet; Lesnick, John; Lewis, Cristina; Mathieu, Simon; Nonomiya, Jim; Shuttleworth, Stephen; Sutherlin, Daniel P.; Wan, Nan Chi; Wang, Shumei; Wiesmann, Christian; Zhu, Bing-Yan published the artcile< Rational Design of Phosphoinositide 3-Kinase α Inhibitors That Exhibit Selectivity over the Phosphoinositide 3-Kinase β Isoform>, Synthetic Route of 18740-39-1, the main research area is PI3K alpha inhibitor preparation antitumor.

Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kβ selectivity for two chem. series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kβ. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Synthetic Route of 18740-39-1.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Zhu, Wufu; Chen, Chen; Sun, Chengyu; Xu, Shan; Wu, Chunjiang; Lei, Fei; Xia, Hui; Tu, Qidong; Zheng, Pengwu published the artcile< Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors>, Recommanded Product: 2,4-Dichlorothieno[2,3-d]pyrimidine, the main research area is thienopyrimidine preparation mTOR PI3Kalpha inhibitor treatment cancer; hydrazinylthienopyrimidine chromenecarboxaldehyde condensation; Chromone; Cytotoxicity; Docking; PI3Kα; Synthesis; Thienopyrimidine; mTOR.

Two series of thienopyrimidine derivatives, e.g, I and II, bearing chromone moiety were designed and synthesized. All the compounds were evaluated for inhibitory activity against mTOR kinase at a concentration of 10uM. Four selected compounds were further evaluated for the IC50 values against mTOR kinase, PI3Kα kinase and two cancer cell lines. One of the target compounds exhibited moderate to excellent mTOR/PI3Kα kinase inhibitory activity and cytotoxicity. The most promising compound II showed good inhibitory activity against mTOR/PI3Kα kinase and good antitumor potency for H460 and PC-3 cell lines with IC50 values of 0.16 ± 0.03 μM, 2.35 ± 0.19 μM, 1.20 ± 0.23 μM and 0.85 ± 0.04 μM, which were 8.6, >5, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 μM, >10 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), resp. Structure-activity relationships (SARs) and docking studies indicated that the chromone moiety is necessary for the potent antitumor activity and cytotoxicity of these compounds Substitution of the chromone moiety at the 6-position has a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Recommanded Product: 2,4-Dichlorothieno[2,3-d]pyrimidine.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Roecker, Anthony J.; Mercer, Swati P.; Harrell, C. Meacham; Garson, Susan L.; Fox, Steven V.; Gotter, Anthony L.; Prueksaritanont, Thomayant; Cabalu, Tamara D.; Cui, Donghui; Lemaire, Wei; Winrow, Christopher J.; Renger, John J.; Coleman, Paul J. published the artcile< Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis>, Product Details of C6H2Cl2N2S, the main research area is orexin receptor antagonist sleep acetonitrile diphosgene dichloropyrimidine; Antagonist; Bioactivation; Orexin; Pyrimidine; Sleep.

Recent clin. studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclin. and clin. sleep efficacy. Addnl. SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat.

Bioorganic & Medicinal Chemistry Letters published new progress about Drug bioavailability. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Product Details of C6H2Cl2N2S.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Watterson, Scott H.; Xiao, Zili; Dodd, Dharmpal S.; Tortolani, David R.; Vaccaro, Wayne; Potin, Dominique; Launay, Michele; Stetsko, Dawn K.; Skala, Stacey; Davis, Patric M.; Lee, Deborah; Yang, Xiaoxia; McIntyre, Kim W.; Balimane, Praveen; Patel, Karishma; Yang, Zheng; Marathe, Punit; Kadiyala, Pathanjali; Tebben, Andrew J.; Sheriff, Steven; Chang, Chieh Ying Y.; Ziemba, Theresa; Zhang, Huiping; Chen, Bang-Chi; DelMonte, Albert J.; Aranibar, Nelly; McKinnon, Murray; Barrish, Joel C.; Suchard, Suzanne J.; Murali Dhar, T. G. published the artcile< Small Molecule Antagonist of Leukocyte Function Associated Antigen-1 (LFA-1): Structure-Activity Relationships Leading to the Identification of 6-((5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic Acid (BMS-688521)>, Safety of Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is spirocyclic hydantoin derivative preparation LFA1 antagonist SAR.

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or αLβ2, belongs to the β2 integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion mols. 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclin. animal studies and clin. data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunol. target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clin. compound (1, I), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clin. trials.

Journal of Medicinal Chemistry published new progress about Homo sapiens. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Safety of Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Vikram, Venugopalarao; Amperayani, Karteek rao; Ummidi, Venkata Ravi Sankar; Parimi, Umadevi published the artcile< Synthesis, Anti-Microbial Activity, and Docking Studies of Novel N-Pyridine Substituted 2-Chlorothieno[2,3-d]pyrimidine Derivatives>, Synthetic Route of 18740-39-1, the main research area is pyridine substituted chloro thienopyrimidinamine preparation antibacterial antifungal docking; acetyl coenzyme carboxylase inhibitor pyridine substituted chloro thienopyrimidinamine preparation.

A series of novel N-pyridine substituted 2-chloro-thieno[2,3-d]pyrimidin-4-amine derivatives I [Ar = 2-pyridyl, (3-methyl-2-pyridyl), (5-chloro-2-pyridyl), etc.] had been synthesized and characterized by 1H and 13C NMR spectrometry. All the compounds had been docked against acetyl-CoA carboxylase enzyme and also tested for their in vitro antimicrobial activity on Gram-pos. (Micrococcus luteus, staphylococcus aureus) and Gram-neg. bacteria (Salmonella typhi, klebsiella pneumoniae) and anti-fungal activity on aspergillus niger and fusarium oxysporum. All synthesized compounds have demonstrated moderate activity and two products have exhibited good antibacterial and antifungal activity.

Russian Journal of General Chemistry published new progress about Acetyl-coenzyme A carboxylase inhibitors. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Synthetic Route of 18740-39-1.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia