Category: pyrimidines

Bellenie, Benjamin R.; Cheung, Kwai-Ming J.; Varela, Ana; Pierrat, Olivier A.; Collie, Gavin W.; Box, Gary M.; Bright, Michael D.; Gowan, Sharon; Hayes, Angela; Rodrigues, Matthew J.; Shetty, Kartika N.; Carter, Michael; Davis, Owen A.; Henley, Alan T.; Innocenti, Paolo; Johnson, Louise D.; Liu, Manjuan; de Klerk, Selby; Le Bihan, Yann-Vai; Lloyd, Matthew G.; McAndrew, P. Craig; Shehu, Erald; Talbot, Rachel; Woodward, Hannah L.; Burke, Rosemary; Kirkin, Vladimir; van Montfort, Rob L. M.; Raynaud, Florence I.; Rossanese, Olivia W.; Hoelder, Swen published the artcile< Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders>, Formula: C5H4Cl2N2S, the main research area is preparation benzimidazolone inhibitor BCL6 interaction repressor lymphoma.

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 99469-85-9 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2S, Formula: C5H4Cl2N2S.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Woodring, Jennifer L.; Bachovchin, Kelly A.; Brady, Kimberly G.; Gallerstein, Mitchell F.; Erath, Jessey; Tanghe, Scott; Leed, Susan E.; Rodriguez, Ana; Mensa-Wilmot, Kojo; Sciotti, Richard J.; Pollastri, Michael P. published the artcile< Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation>, Product Details of C4H2Br2N2, the main research area is anilinoquinazoline trypanosome inhibitor antimalarial malaria trypanosomiasis trypanosomicide; Human African trypanosomiasis; Leishmania major; Neglected tropical disease; Plasmodium falciparum; Target class repurposing; Trypanosoma brucei; Trypanosoma cruzi.

Human African trypanosomiasis (HAT) is a deadly disease in need of new chemotherapeutics that can cross into the central nervous system. The authors previously reported the discovery of (NEU-617), a small mol. with activity against T. brucei bloodstream proliferation. Further optimization of NEU-617 to improve the physicochem. properties (LogP, LLE, [1], and MPO score) [2] have led us to twelve sub-micromolar compounds, most importantly the headgroup variants I and II, and the linker variant III. Although these 3 compounds had reduced potency compared to NEU-617, they all had improved LogP, LLE and MPO scores. Cross-screening these analogs against other protozoan parasites uncovered IV with potent activity towards T. brucei, T. cruzi and L. major, while four others compounds showed activity towards P. falciparum D6. This reinforces the effectiveness of lead repurposing for the discovery of new protozoan disease therapeutics.

European Journal of Medicinal Chemistry published new progress about Antimalarials. 3921-01-5 belongs to class pyrimidines, and the molecular formula is C4H2Br2N2, Product Details of C4H2Br2N2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Kickinger, Stefanie; Al-Khawaja, Anas; Haugaard, Anne Staehr; Lie, Maria E. K.; Bavo, Francesco; Loeffler, Rebekka; Damgaard, Maria; Ecker, Gerhard F.; Froelund, Bente; Wellendorph, Petrine published the artcile< Exploring the molecular determinants for subtype-selectivity of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid analogs as betaine/GABA transporter 1 (BGT1) substrate-inhibitors>, Application of C7H7ClN2O2, the main research area is amino tetrahydropyrimidine carboxylic acid betaine GABA transporter substrate inhibitor.

We have previously identified 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid (ATPCA) as the most potent substrate-inhibitor of the betaine/GABA transporter 1 (BGT1) (IC50 2.5 μM) reported to date. Herein, we characterize the binding mode of 20 novel analogs and propose the mol. determinants driving BGT1-selectivity. A series of N1-, exocyclic-N-, and C4-substituted analogs was synthesized and pharmacol. characterized in radioligand-based uptake assays at the four human GABA transporters (hGATs) recombinantly expressed in mammalian cells. Overall, the analogs retained subtype-selectivity for hBGT1, though with lower inhibitory activities (mid to high micromolar IC50 values) compared to ATPCA. Further characterization of five of these BGT1-active analogs in a fluorescence-based FMP assay revealed that the compounds are substrates for hBGT1, suggesting they interact with the orthosteric site of the transporter. In silico-guided mutagenesis experiments showed that the non-conserved residues Q299 and E52 in hBGT1 as well as the conformational flexibility of the compounds potentially contribute to the subtype-selectivity of ATPCA and its analogs. Overall, this study provides new insights into the mol. interactions governing the subtype-selectivity of BGT1 substrate-inhibitors. The findings may guide the rational design of BGT1-selective pharmacol. tool compounds for future drug discovery.

Scientific Reports published new progress about Aminopyrimidines Role: PAC (Pharmacological Activity), PRP (Properties), SPN (Synthetic Preparation), THU (Therapeutic Use), BIOL (Biological Study), PREP (Preparation), USES (Uses). 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Application of C7H7ClN2O2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Nakazawa, Junichi; Watatani, Mitsuo published the artcile< Pyrimidine derivatives. II. Transetherification in pyrimidine derivatives>, COA of Formula: C5H6ClN3O, the main research area is .

Transetherification reactions of 2-methoxy-, 2-ethoxy-4-amino-6-chloropyrimidine, and 2,6-dimethoxy- and 2,6-diethoxy-4-aminopyrimidine at the alkoxy groups at 2- and 6-position by the treatment with NaOMe or NaOEt were investigated and found that the 2-position was more reactive than 4-position and the MeO group more readily underwent transetherification reaction than the EtO group. In 5-substituted pyrimidines with an electroneg. group, the MeOH at 2-, 4-, or 6-position was readily eliminated owing to its further higher reactivity. Manufacture of the following new compounds was also described: a mixture of 38.4 g. barbituric acid 24.3 g. KCN and 144 g. urea was melted at 143-8° 4 hrs., then cooled to 100°, 240 cc. H2O added, stirred 30 min., cooled to below 50°, acidified with HCl, and filtered to give 56.5 g. 2,4,6-trihydroxy-5-pyrimidinecarboxamide (I), fiberlike crystals, m. above 360°. I (8.6 g.) was refluxed with 61 g. POCl3 and 6 g. PhNMe2 1.5 hrs., decomposed with ice, extracted with C6H6, the extract evaporated, and the residue purified by sublimation to give 2,4,6-trichloro-5-cyanopyrimidine (II), plates, m. 122-3.5°. II (1 g.) was added to a solution of 0.67 g. Na in 30 cc. MeOH, refluxed 4 hrs., filtered, the filtrate concentrated, H2O added, and the whole neutralized with HCl to give 2,4-dimethoxy-5-cyano-6-hydroxypyrimidine (III), needles, m. 217-18° (decomposition) (MeOH). III (0.3 g.) was heated 2 hrs. with 30 cc. 5% KOH solution on a steam bath, acidified with HCl, and the mixture filtered to give 2,4,6-trihydroxy-5-cyanopyrimidine, m. above 360°.

Takamine Kenkyusho Nenpo published new progress about Alcoholysis. 3286-55-3 belongs to class pyrimidines, and the molecular formula is C5H6ClN3O, COA of Formula: C5H6ClN3O.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Sagong, Hye Yeon; Bauman, Joseph D.; Patel, Disha; Das, Kalyan; Arnold, Eddy; LaVoie, Edmond J. published the artcile< Phenyl Substituted 4-Hydroxypyridazin-3(2H)-ones and 5-Hydroxypyrimidin-4(3H)-ones: Inhibitors of Influenza A Endonuclease>, Application of C5H4Cl2N2O, the main research area is aryl hydroxypyridazinone preparation influenza A endonuclease inhibitor antiviral; hydroxypyrimidinone aryl preparation influenza A endonuclease inhibitor antiviral.

Seasonal and pandemic influenza outbreaks remain a major human health problem. Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is attractive for the development of new agents for the treatment of influenza infection. Authors’ earlier studies identified a series of 5- and 6-Ph substituted 3-hydroxypyridin-2(1H)-ones that were effective inhibitors of influenza endonuclease. These agents identified as bimetal chelating ligands binding to the active site of the enzyme. In the present study, several aza analogs of these Ph substituted 3-hydroxypyridin-2(1H)-one compounds were synthesized and evaluated for their ability to inhibit the endonuclease activity. In contrast to the 4-aza analog of 6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one, the 5-aza analog (5-hydroxy-2-(4-fluorophenyl)pyrimidin-4(3H)-one) did exhibit significant activity as an endonuclease inhibitor. The 6-aza analog of 5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one (6-(4-fluorophenyl)-4-hydroxypyridazin-3(2H)-one) also retained modest activity as an inhibitor. Several varied 6-phenyl-4-hydroxypyridazin-3(2H)-ones and 2-phenyl-5-hydroxypyrimidin-4(3H)-ones, e.g., I (X-rays crystal structure in complex with endonuclease shown), were synthesized and evaluated as endonuclease inhibitors. The SAR observed for these aza analogs are consistent with those previously observed with various Ph substituted 3-hydroxypyridin-2(1H)-ones.

Journal of Medicinal Chemistry published new progress about Antiviral agents. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Application of C5H4Cl2N2O.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

McGee, Danny P. C.; Martin, John C.; Verheyden, Julien P. H. published the artcile< Synthesis of the 7-deaza and 5-aza-7-deaza purine analogs of the antiherpes agent 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG)>, Recommanded Product: 4-Methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine, the main research area is pyrrolopyrimidinone acyclic nucleoside analog; imidazotriazinone acyclic nucleoside analog; acyclic nucleoside pyrrolopyrimidinone imidazotriazinone; virucide acyclic nucleoside; DHPG analog; hydroxypyropoxymethylpyrrolopyrimidinone amino; hydroxypropoxymethylimidazotriazinone amino.

DHPG analogs I and II were prepared Reaction of 2-amino-4-methoxypyrrolo[2,3-d]pyrimidine with 1,3-dibenzyloxy-2-(chloromethyl)glycerol under phase-transfer conditions gave a product which on sequential treatment with p-MeC6H4SK (to cleave the Me ether) and BBr3 (for debenzylation) gave I. Reaction of 2-acetamidoimidazo[1,2-a]-s-triazin-4-one with 1,3-dibenzyloxy-2-(acetoxymetyl)glycerol gave a product, which on debenzylation (by catalytic transfer hydrogenation) and then deacetylation gave II. I and II were inactive against herpes simplex virus types I and II in cell culture.

Journal of Heterocyclic Chemistry published new progress about Antiviral agents. 84955-32-8 belongs to class pyrimidines, and the molecular formula is C7H8N4O, Recommanded Product: 4-Methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Zhang, Xuqing; Zhu, Bin; Sun, Weimei; Wang, Mina; Albarazanji, Kamal; Ghosh, Brahma; Cummings, Maxwell; Lenhard, James; Leonard, James; Macielag, Mark; Lanter, James published the artcile< Discovery of a novel series of guanidinebenzoates as gut-restricted enteropeptidase and trypsin dual inhibitors for the treatment of metabolic syndrome>, Recommanded Product: Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is guanidinebenzoates gutrestricted enteropeptidase trypsin dual inhibitor treatment metabolic syndrome; Enteropeptidase inhibitor; Guanidinebenzoate; Gut-restriction; Trypsin inhibitor.

Novel series of guanidinebenzoate enteropeptidase and trypsin dual inhibitors has been discovered and SAR studies were conducted. Optimization was focused on improving properties for gut restriction, including increased aqueous solubility, lower cellular permeability, and reduced oral bioavailability. Lead compounds were identified with efficacy in a mouse fecal protein excretion study.

Bioorganic & Medicinal Chemistry Letters published new progress about Biological permeation. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Recommanded Product: Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Choi, Chulho; Nuhant, Philippe; Mousseau, James J.; Yang, Xiaojing; Gerstenberger, Brian S.; Williams, Jessica M.; Wright, Stephen W. published the artcile< Synthesis of Chiral Azabicycles from Pyroglutaminols>, Formula: C7H7ClN2O2, the main research area is chiral azabicycle morpholine piperazine derivative preparation; stereocontrolled intramol SN2 cyclization pyroglutaminol.

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramol. SN2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery.

Organic Letters published new progress about Cyclization, stereoselective. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Formula: C7H7ClN2O2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Fang, Yuanying; Zhang, Shaokun; Li, Min; Xiong, Lijuan; Tu, Liangxing; Xie, Saisai; Jin, Yi; Liu, Yanhua; Yang, Zunhua; Liu, Ronghua published the artcile< Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists>, Application of C5H4Cl2N2O, the main research area is dihydropyrimido oxazine derivative preparation GPR 119 agonist diabetes; GPR 119 agonists; Optimisation; pyrimidodihydrooxazine; type 2 diabetes mellitus.

GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimization of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound and demonstrated the potent EC50 values (13 and 12 nM, resp.) and strong inherent activities. Moreover, significant hypoglycemic effect of compound was observed by reducing the blood glucose AUC0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).

Journal of Enzyme Inhibition and Medicinal Chemistry published new progress about Antidiabetic agents. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Application of C5H4Cl2N2O.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Jung, Seung-Youn; Nam, Ky-Youb; Park, Jeong-In; Song, Kyung-Hee; Ahn, Jiyeon; Park, Jong Kuk; Um, Hong-Duck; Hwang, Sang-Gu; Choi, Sang Un; Song, Jie-Young published the artcile< Radiosensitizing effect of novel phenylpyrimidine derivatives on human lung cancer cells via cell cycle perturbation>, Product Details of C4H2Br2N2, the main research area is lung cancer cell phenylpyrimidine derivative radiosensitizing.

Radiotherapy is one of the most common treatments for cancer, but radioresistance and injury to normal tissue are considered major obstacles to successful radiotherapy. Thus, there is an urgent need to develop radiosensitizers to improve the therapeutic outcomes of radiotherapy in cancer patients. Our previous efforts to identify novel radiosensitizers, using high-throughput screening targeting p53 and Nrf2 revealed a promising N-phenylpyrimidin-2-amine (PPA) lead compound; 17 derivatives of this lead compound were examined in the present study. PPA5, 13, 14, 15, and 17 inhibited cell viability by more than 50% with a marked increase in the proportion of cells arrested at the G2/M phase of cell cycle. Among these compounds, PPA15 markedly increased the sub-G1 cell population and increased the levels of cyclin B1 and phosphorylation levels of cyclin-dependent kinases 1 (CDK1). Combined treatment with radiation and PPA14 or PPA15 significantly decreased clonogenic survival. An in vitro kinase assay revealed that PPA15 inhibited multiple CDKs involved in cell cycle regulation. Compared with drug or radiation treatment alone, combined treatment with PPA15 and radiation resulted in the suppression of A549 tumor growth in mice by 59.5% and 52.7%, resp. Treatment with PPA15 alone directly inhibited tumor growth by 25.7%. These findings suggest that the novel pan CDK inhibitor, PPA15, may be a promising treatment to improve the effectiveness of radiotherapy for the treatment of cancer.

Journal of Pharmacology and Experimental Therapeutics published new progress about Apoptosis. 3921-01-5 belongs to class pyrimidines, and the molecular formula is C4H2Br2N2, Product Details of C4H2Br2N2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia