Day: November 29, 2022

Caroff, Eva published the artcileOptimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y₁₂ antagonists for inhibition of platelet aggregation, Recommanded Product: 1H-Pyrazole-4-boronic acid, the publication is Bioorganic & Medicinal Chemistry Letters (2014), 24(17), 4323-4331, database is CAplus and MEDLINE.

2-Phenyl-4-pyrimidinecarboxamide analogs were identified as P2Y₁₂ antagonists. Optimization of the carbon-linked or nitrogen-linked substituent at the 6-position of the pyrimidine ring provided compounds with excellent ex vivo potency in the platelet aggregation assay in human plasma. One compound met the objectives for activity, selectivity and ADMET properties. The synthesis of the target compounds was achieved using (γS)-γ-[[(6-chloro-2-phenyl-4-pyrimidinyl)carbonyl]amino]-4-(ethoxycarbonyl)-δ-oxo-1-piperazinepentanoic acid 1,1-dimethylethyl ester and (γS)-4-(butoxycarbonyl)-γ-[[(6-chloro-2-phenyl-4-pyrimidinyl)carbonyl]amino]-δ-oxo-1-piperazinepentanoic acid 1,1-dimethylethyl ester as key intermediates.

Bioorganic & Medicinal Chemistry Letters published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Recommanded Product: 1H-Pyrazole-4-boronic acid.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Bachmann, Fabio published the artcileCytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine, Computed Properties of 930-36-9, the publication is British Journal of Clinical Pharmacology (2022), 88(4), 1885-1896, database is CAplus and MEDLINE.

Metamizole (dipyrone) is a prodrug not detectable in serum or urine after oral ingestion. The primary metabolite, 4-methylaminoantipyrine (4-MAA), can be N-demethylated to 4-aminoantipyrine (4-AA) or oxidized to 4-formylaminoantipyrine (4-FAA) by cytochrome P 450 (CYP)-dependent reactions. We aimed to identify the CYPs involved in 4-MAA metabolism and to quantify the effect of CYP inhibition on 4-MAA metabolism We investigated the metabolism of 4-MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in male subjects. The experiments in supersomes revealed CYP1A2 as the major CYP for 4-MAA N-demethylation and 4-FAA formation with CYP2C19 and CYP2D6 contributing to N-demethylation. In the clin. study, we investigated the influence of ciprofloxacin (CYP1A2 inhibitor), fluconazole (CYP2C19 inhibitor) and the combination ciprofloxacin/fluconazole on the pharmacokinetics of metamizole in n = 12 male subjects in a randomized, placebo-controlled, double-blind study. The geometric mean ratios for the area under the concentration-time curve of 4-MAA after/before treatment were 1.17 (90% CI 1.09-1.25) for fluconazole, 1.51 (90% CI 1.42-1.60) for ciprofloxacin and 1.92 (90% CI 1.81-2.03) for ciprofloxacin/fluconazole. Fluconazole increased the half-life of 4-MAA from 3.22 h by 0.47 h (95% CI 0.13-0.81, P < .05), ciprofloxacin by 0.69 h (95% CI 0.44-0.94, P < .001) and fluconazole/ciprofloxacin by 2.85 h (95% CI 2.48-3.22, P < .001). CYP1A2 is the major CYP for the conversion of 4-MAA to 4-AA and 4-FAA. The increase in 4-MAA exposure by the inhibition of CYP1A2 and by the combination CYP1A2/CYP2C19 may be relevant for dose-dependent adverse reactions of 4-MAA.

British Journal of Clinical Pharmacology published new progress about 930-36-9. 930-36-9 belongs to pyrazoles-derivatives, auxiliary class Pyrazole, name is 1-Methylpyrazole, and the molecular formula is C4H6N2, Computed Properties of 930-36-9.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Antolin, Albert A. published the artcileDistant Polypharmacology among MLP Chemical Probes, Quality Control of 71203-35-5, the publication is ACS Chemical Biology (2015), 10(2), 395-400, database is CAplus and MEDLINE.

Small mols. are essential tool compounds to probe the role of proteins in biol. and advance toward more efficient therapeutics. However, they are used without a complete knowledge of their selectivity across the entire proteome, at risk of confounding their effects due to unknown off-target interactions. Current state-of-the-art computational approaches to predicting the affinity profile of small mols. offer a means to anticipate potential nonobvious selectivity liabilities of chem. probes. The application of in silico target profiling on the full set of chem. probes from the NIH Mol. Libraries Program (MLP) resulted in the identification of biol. relevant in vitro affinities for proteins distantly related to the primary targets of ML006, ML123, ML141, and ML204, helping to lower the risk of their further use in chem. biol.

ACS Chemical Biology published new progress about 71203-35-5. 71203-35-5 belongs to pyrazoles-derivatives, auxiliary class GPCR/G Protein,Ras, name is 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide, and the molecular formula is C22H21N3O3S, Quality Control of 71203-35-5.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Desroy, Nicolas published the artcileTowards Gram-negative antivirulence drugs: New inhibitors of HldE kinase, Safety of (1H-Pyrazol-5-yl)boronic acid, the publication is Bioorganic & Medicinal Chemistry (2009), 17(3), 1276-1289, database is CAplus and MEDLINE.

Gram-neg. bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochem. assay suitable for high-throughput screening allowed the discovery of inhibitors 1 and 2 of HldE kinase. Study of the structure-activity relation of this series of inhibitors led to highly potent compounds

Bioorganic & Medicinal Chemistry published new progress about 724710-02-5. 724710-02-5 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Pyrazole,Boronic Acids,Boronic acid and ester, name is (1H-Pyrazol-5-yl)boronic acid, and the molecular formula is C3H5BN2O2, Safety of (1H-Pyrazol-5-yl)boronic acid.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Gavrilenko, B. B. published the artcileReaction of enamines with hydrazine, Safety of Ethyl 5-amino-3-methyl-1H-pyrazole-4-carboxylate, the publication is Zhurnal Organicheskoi Khimii (1974), 10(3), 601-4, database is CAplus.

RR1C:C(NH2)NHNH2 (I; R = CO2Me, CO2Et, CO2Pr, CO2Ph, R1 = CO2Me, CO2Et, CN) were obtained in 78-90% yields by boiling RR1C:C(CCl3)NH2 on a water bath 3-5 min. Pyrazoles (II; R1 = CO2Et, CO2Pr, CO2Ph) were obtained in 80-95% yields by cyclization of the appropriate I (R = CN) in DMF containing N2H4.H2O. Analogous obtained were 70-98% pyrazoles (III; R1 = H, CO2Et,R3 = Me). Acylaminopyrazoles (IV; R1 = H, CO2Et, CO2Pr,R3 = Me, Ph, NH2, AcNH) were addnl. obtained in 78-96% yields.

Zhurnal Organicheskoi Khimii published new progress about 23286-70-6. 23286-70-6 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Amine,Ester, name is Ethyl 5-amino-3-methyl-1H-pyrazole-4-carboxylate, and the molecular formula is C7H11N3O2, Safety of Ethyl 5-amino-3-methyl-1H-pyrazole-4-carboxylate.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Faid-Allah, Hassan M. published the artcilePyrazole derivatives with possible hypoglycemic activity, Synthetic Route of 71203-35-5, the publication is Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1988), 27B(3), 245-9, database is CAplus.

Condensation reaction of p-H₂NSO₂C₆H₄NHNH₂.HCl with p-RC₆H₄CH:CHCOC₆H₄R¹–p (R = H, R¹ = OMe, Cl, Br, NH₂; R = MeO, R¹ = H) gave the corresponding hydrazones in the presence of NaOAc; in the absence of NaOAc, the products were pyrazolines I (R² = H). Oxidation of I with Br gave pyrazoles II (R² = H). Acylation and thioacylation of I and II with R³NCX (R³ = Pr, Bu, Ph, cyclohexyl, X = O; R³ = allyl, Ph, cyclohexyl, PhCH₂, X = S) gave ureas and thioureas I and II [R² = CXNHR³]. Cyclocondensation of II (R² = CSNHR³) with Br(CH₂)_nCO₂Et (n = 1,2) gave imino heterocycles III.

Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry published new progress about 71203-35-5. 71203-35-5 belongs to pyrazoles-derivatives, auxiliary class GPCR/G Protein,Ras, name is 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide, and the molecular formula is C22H21N3O3S, Synthetic Route of 71203-35-5.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Zhang, Lingtian published the artcileDiscovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose, Name: 1-Methylpyrazole, the publication is Journal of Medicinal Chemistry (2022), 65(2), 1536-1551, database is CAplus and MEDLINE.

Mutations of the rearranged during transfection (RET) kinase are frequently reported in cancer, which make it as an attractive therapeutic target. Herein, we discovered a series of N-trisubstituted pyrimidine derivatives as potent inhibitors for both wild-type (weight) RET and RET^V804M, which is a resistant mutant for several FDA-approved inhibitors. The X-ray structure of a representative inhibitor with RET revealed that the compound binds in a unique pose that bifurcates beneath the P-loop and confirmed the compound as a type I inhibitor. Through the structure-activity relationship (SAR) study, compound 20 (I) was identified as a lead compound, showing potent inhibition of both RET and RET^V804M. Addnl., compound 20 displayed potent antiproliferative activity of CCDC6-RET-driven LC-2/ad cells. Anal. of RET phosphorylation indicated that biol. activity was mediated by RET inhibition. Collectively, N-trisubstituted pyrimidine derivatives could serve as scaffolds for the discovery and development of potent inhibitors of type I RET and its gatekeeper mutant for the treatment of RET-driven cancers.

Journal of Medicinal Chemistry published new progress about 930-36-9. 930-36-9 belongs to pyrazoles-derivatives, auxiliary class Pyrazole, name is 1-Methylpyrazole, and the molecular formula is C9H6N2O2, Name: 1-Methylpyrazole.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Li, Yun published the artcileA Metal-Ligand Layer Compatible with Various Types of Pillars for New Porous Coordination Polymers, Computed Properties of 19959-71-8, the publication is Crystal Growth & Design (2020), 20(10), 7021-7026, database is CAplus.

Pillared-layer structures are classic for porous coordination polymers (PCPs), but suitable metal-ligand layers for such structures are rare. Here, the authors report a cationic {Zn₂(pzdc)}⁺ (H₃pzdc = 3,5-pyrazoledicarboxylic acid) layer compatible with various types of pillar ligands. Solvothermal reactions of Zn(NO₃)₂·6H₂O and H₃pzdc with 4-(pyridin-4-yl)-1H-pyrazole (Hpypz), 1,4-benzenedicarboxylic acid (H₂bdc), or 2-amino-1,4-benzenedicarboxylic acid (H₂abdc) in a mixed solvent of H₂O and N,N-dimethylformamide (DMF) produced three pillared-layer PCPs, namely [Zn₄(pzdc)₂(pypz)₂]·guest (1), [Zn₄(pzdc)₂(bdc)(H₂O)_1.53(DMF)_0.47]·guest (2), and [Zn₄(pzdc)₂(abdc)(H₂O)_1.52(DMF)_0.48]·guest (3), resp. Single-crystal X-ray analyses revealed that the {Zn₂(pzdc)}⁺ layers are fully pillared by pypz^– in 1 and half pillared by bdc^2- and abdc^2- in 2 and 3, because the anionic pillars possess different charges. Consequently, 1 shows one-dimensional (1D) channels with a small porosity and 2 and 3 show 2D channels with large porosities, both of which were verified by N₂ and CO₂ adsorption isotherms. While 1 has no coordinated solvent mols. and exhibits a high water stability, 2 and 3 possess coordinated solvent mols. and quickly transform to crystals of 2D coordination networks in water, [Zn₄(pzdc)₂(OH)₂(H₂O)₆]·H₂bdc·4H₂O (4) and [Zn₄(pzdc)₂(H₂abdc)(OH)₂(H₂O)₅]·2H₂O (5), resp., which can be further exfoliated into ultrathin nanosheets in an ammonia solution A new metal-ligand layer can adopt various types of pillars to give a series of pillared-layer PCPs with tunable pillar densities, porosities, and water stabilities. The water-instable ones can be exfoliated to ultrathin nanosheets with intermediates suitable for single-crystal diffraction characterization.

Crystal Growth & Design published new progress about 19959-71-8. 19959-71-8 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Pyridine, name is 4-(1H-Pyrazol-4-yl)pyridine, and the molecular formula is C8H7N3, Computed Properties of 19959-71-8.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Kamasaki, Tomoko published the artcileFBP17-mediated finger-like membrane protrusions in cell competition between normal and RasV12-transformed cells, Recommanded Product: 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide, the publication is iScience (2021), 24(9), 102994, database is CAplus and MEDLINE.

At the initial stage of carcinogenesis, cell competition often occurs between newly emerging transformed cells and the neighboring normal cells, leading to the elimination of transformed cells from the epithelial layer. For instance, when RasV12-transformed cells are surrounded by normal cells, RasV12 cells are apically extruded from the epithelium. However, the underlying mechanisms of this tumor-suppressive process still remain enigmatic. We first show by electron microscopic anal. that characteristic finger-like membrane protrusions are projected from both normal and RasV12 cells at their interface. In addition, FBP17, a member of the F-BAR proteins, accumulates in RasV12 cells, as well as surrounding normal cells, which plays a pos. role in the formation of finger-like protrusions and apical elimination of RasV12 cells. Furthermore, cdc42 acts upstream of these processes. These results suggest that the cdc42/FBP17 pathway is a crucial trigger of cell competition, inducing “protrusion to protrusion response” between normal and RasV12-transformed cells.

iScience published new progress about 71203-35-5. 71203-35-5 belongs to pyrazoles-derivatives, auxiliary class GPCR/G Protein,Ras, name is 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide, and the molecular formula is C22H21N3O3S, Recommanded Product: 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Ariyani, Winda published the artcileGadolinium-based contrast agent accelerates the migration of astrocyte via integrin αvβ3 signaling pathway, Quality Control of 71203-35-5, the publication is Scientific Reports (2022), 12(1), 5850, database is CAplus and MEDLINE.

Gadolinium (Gd)-based contrast agents (GBCAs) are chems. injected i.v. during magnetic resonance imaging to enhance the diagnostic yield. Repeated use of GBCAs causes their deposition in the brain. Such deposition may affect various neuronal cells, including astrocytes. In this study, we examined the effect of GBCAs (Omniscan, Magnescope, Magnevist, and Gadovist) on astrocyte migration, which is critical for formation of neurons during development and maintaining brain homeostasis. All GBCAs increased cell migration and adhesion with increased actin remodelling. Knockdown of integrin αvβ3 by RNAi or exposure to integrin αvβ3 inhibitor reduced astrocyte migration. GBCAs increased phosphorylation of downstream factors of αvβ3, such as FAK, ERK1/2, and Akt. The phosphorylation of all these factors were reduced by RNAi or integrin αvβ3 inhibitor. GBCAs also increased the phosphorylation of their downstream factor, Rac1/cdc42, belonging to the RhoGTPases family. Coexposure to the selective RhoGTPases inhibitors, decreased the effects of GBCAs on cell migration. These findings indicate that GBCAs exert their action via integrin αvβ3 to activate the signaling pathway, resulting in increased astrocyte migration. Thus, the findings of the study suggest that it is important to avoid the repeated use of GBCAs to prevent adverse side effects in the brain, particularly during development.

Scientific Reports published new progress about 71203-35-5. 71203-35-5 belongs to pyrazoles-derivatives, auxiliary class GPCR/G Protein,Ras, name is 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide, and the molecular formula is C22H21N3O3S, Quality Control of 71203-35-5.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics