Category: 56-05-3

Gower, Carrie M. published the artcileConversion of a Single Polypharmacological Agent into Selective Bivalent Inhibitors of Intracellular Kinase Activity, Recommanded Product: 2-Amino-4,6-dichloropyrimidine, the publication is ACS Chemical Biology (2016), 11(1), 121-131, database is CAplus and MEDLINE.

Loss-of-function studies are valuable for elucidating kinase function and the validation of new drug targets. While genetic techniques, such as RNAi and genetic knockouts, are highly specific and easy to implement, in many cases post-translational perturbation of kinase activity, specifically pharmacol. inhibition, is preferable. However, due to the high degree of structural similarity between kinase active sites and the large size of the kinome, identification of pharmacol. agents that are sufficiently selective to probe the function of a specific kinase of interest is challenging, and there is currently no systematic method for accomplishing this goal. Here, the authors present a modular chem. genetic strategy that uses antibody mimetics as highly selective targeting components of bivalent kinase inhibitors. The authors demonstrate that it is possible to confer high kinase selectivity to a promiscuous ATP-competitive inhibitor by tethering it to an antibody mimetic fused to the self-labeling protein SNAPtag. With this approach, a potent bivalent inhibitor of the tyrosine kinase Abl was generated. Profiling in complex cell lysates, with competition-based quant. chem. proteomics, revealed that this bivalent inhibitor possesses greatly enhanced selectivity for its target, BCR-Abl, in K562 cells. Importantly, the authors show that both components of the bivalent inhibitor can be assembled in K562 cells to block the ability of BCR-Abl to phosphorylate a direct cellular substrate. Finally, the authors demonstrate the generality of using antibody mimetics as components of bivalent inhibitors by generating a reagent that is selective for the activated state of the serine/threonine kinase ERK2.

ACS Chemical Biology published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Recommanded Product: 2-Amino-4,6-dichloropyrimidine.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Ruiz Ruiz, Maria del Carmen published the artcileThe ‘t-Amino Effect’ of ortho-nitroso amines. synthesis of 2,6-diaminoadenine derivatives from 6-(dialkylamino)-5-nitrosopyrimidines, Safety of 2-Amino-4,6-dichloropyrimidine, the publication is Helvetica Chimica Acta (2011), 94(5), 785-800, database is CAplus.

The ‘t-amino effect’ of amino-nitroso compounds was documented by preparing the (dialkylamino)-nitroso pyrimidines, and cyclising them under thermal conditions in high yields to the purine derivatives e. g., I(R¹ = Me, R² = H, Me, Pr, Ph; R¹ = Et, R² = Me; R¹ = CO₂Et, R² = CH₂CO₂Et) and II. The reactivity of the amino-nitroso-pyrimidines, particularly of 17 derived from di-Et iminodiacetate, and of I(R¹ = CO₂Et, R² = CH₂CO₂Et), derived from 1-phenylimidazolidine, correlates with the stability of the intermediate azomethine ylide. Thermolysis of the amino-nitroso-pyrimidines III(R¹ = NO, R² = 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 4-Et isonipecotate-1yl) possessing dialkylamino substituents at C(4) and C(6), proceeded by protiodenitrosation, leading to III(R¹ = H, R² = 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 4-Et isonipecotate-1yl).

Helvetica Chimica Acta published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Safety of 2-Amino-4,6-dichloropyrimidine.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Giordanetto, Fabrizio published the artcileDiscovery of phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, an effective antithrombotic agent without associated bleeding and insulin resistance, SDS of cas: 56-05-3, the publication is Bioorganic & Medicinal Chemistry Letters (2012), 22(21), 6671-6676, database is CAplus and MEDLINE.

Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor with favorable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Addnl., due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.

Bioorganic & Medicinal Chemistry Letters published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, SDS of cas: 56-05-3.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Santandrea, Ernesto published the artcileDevelopment of the Late-Phase Manufacturing Process of ZPL389: Control of Process Impurities by Enhanced Process Knowledge, Product Details of C4H3Cl2N3, the publication is Organic Process Research & Development (2021), 25(5), 1190-1205, database is CAplus.

The development of the late-phase manufacturing process of the drug candidate ZPL389 and the strategies for the control of impurities are outlined in detail. Selective salt formation at several stages was pivotal to controlling the process impurities. The extensive optimization of the N-methylation of a Boc-protected amine with di-Me sulfate and of a nucleophilic aromatic substitution without the use of metal catalysts led to a robust, scalable process. The process was demonstrated on a >100 kg scale. Overall, improved drug substance quality, higher yield, and reduction of the process mass intensity were achieved.

Organic Process Research & Development published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Product Details of C4H3Cl2N3.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Kang, Yanlong published the artcileHeat Shock Protein 70 Inhibitors. 1. 2,5′-Thiodipyrimidine and 5-(Phenylthio)pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70, Related Products of pyrimidines, the publication is Journal of Medicinal Chemistry (2014), 57(4), 1188-1207, database is CAplus and MEDLINE.

Heat shock protein 70 (Hsp70) is an important emerging cancer target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure-activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5′-thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives 17a and 20a, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics.

Journal of Medicinal Chemistry published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Related Products of pyrimidines.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Camacho-Hernandez, Gisela Andrea published the artcileSynthesis, pharmacological characterization, and structure-activity relationships of non-canonical selective agonists for α7 nAChRs, Application of 2-Amino-4,6-dichloropyrimidine, the publication is Journal of Medicinal Chemistry (2019), 62(22), 10376-10390, database is CAplus and MEDLINE.

Noncanonical 2,4,6-substituted pyrimidine analogs were prepared for a structure-activity relationship study. The new lead compounds activate selectively the α7 nAChRs with EC₅₀‘s between 30-140 nM in a PNU-120596-dependent, cell-based calcium influx assay. After characterizing the expanded lead landscape, author ranked the compounds for rapid activation using Xenopus oocytes expressing human α7 nAChR with a two-electrode voltage clamp. This approach enabled us to define the mol. determinants governing rapid activation, agonist potency, and desensitization of α7 nAChRs after exposure to pyrimidine analogs, thereby distinguishing this subclass of non-canonical agonists from previously defined types of agonists (agonists, partial agonists, silent agonists, and ago-PAMs). By NMR, author analyzed pKa values for ionization of lead candidates, demonstrating distinctive modes of interaction for this landscape of ligands.

Journal of Medicinal Chemistry published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Application of 2-Amino-4,6-dichloropyrimidine.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Henderson, Scott H. published the artcileDiscovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors, Related Products of pyrimidines, the publication is Journal of Medicinal Chemistry (2021), 64(15), 11709-11728, database is CAplus and MEDLINE.

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer′s disease (AD) and Down′s syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A′s role as a mediator in the cell cycle has garnered interest in oncol. indications. Structure-activity relationship (SAR) anal. in combination with high-resolution X-ray crystallog. leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochem. properties, and a high degree of selectivity over the kinome. Compound 11 (I) exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

Journal of Medicinal Chemistry published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Related Products of pyrimidines.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Hasanein, Ahmed A. published the artcileDFT calculations of amine-imine tautomerism in some pyrimidine derivatives and their 1:1 and 1:2 complexes with water, Category: pyrimidines, the publication is International Journal of Quantum Chemistry (2011), 111(15), 3993-4010, database is CAplus.

Amine-Imine tautomerization in 2-amino-pyrimidine (I), 2-amino-4,6-dichloropyrimidine (II), 2-amino-4,6-dimethylpyrimidine (III), and 2-amino-4,6-dimethoxypyrimidine (IV) and their 1:1 and 1:2 H-bonded complexes with water have been studied using the B3LYP/6-31++G** method. Optimum mol. geometries, electronic properties, and energetics of these systems have been discussed. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011.

International Journal of Quantum Chemistry published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Category: pyrimidines.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Engelhardt, Harald published the artcileBispyrimidines as Potent Histamine H₄ Receptor Ligands: Delineation of Structure-Activity Relationships and Detailed H₄ Receptor Binding Mode, Product Details of C4H3Cl2N3, the publication is Journal of Medicinal Chemistry (2013), 56(11), 4264-4276, database is CAplus and MEDLINE.

The basic methylpiperazine moiety is considered a necessary substructure for high histamine H₄ receptor (H₄R) affinity. This moiety is however also the metabolic hot spot for various classes of H₄R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an addnl. 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pK_i values for binding the human H₄R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homol. modeling leads to new detailed insights in the mol. aspects of ligand-H₄R binding in general and the binding mode of the described bispyrimidines in specific.

Journal of Medicinal Chemistry published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Product Details of C4H3Cl2N3.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Bold, Guido published the artcileA Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis, Synthetic Route of 56-05-3, the publication is Journal of Medicinal Chemistry (2016), 59(1), 132-146, database is CAplus and MEDLINE.

This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochem. and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochem. anal. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

Journal of Medicinal Chemistry published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Synthetic Route of 56-05-3.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia