Category: 20744-39-2

Venkatesan, Aranapakam M.; Dehnhardt, Christoph M.; Delos Santos, Efren; Chen, Zecheng; Dos Santos, Osvaldo; Ayral-Kaloustian, Semiramis; Khafizova, Gulnaz; Brooijmans, Natasja; Mallon, Robert; Hollander, Irwin; Feldberg, Larry; Lucas, Judy; Yu, Ker; Gibbons, James; Abraham, Robert T.; Chaudhary, Inder; Mansour, Tarek S. published the artcile< Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5'-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound 26 (PKI-587), a Highly Efficacious Dual Inhibitor>, Synthetic Route of 20744-39-2, the main research area is PI3K mTOR inhibitor dimorpholinotriazine preparation; triazine dimorpholino preparation PI3K mTOR inhibitor.

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea (PKI-587). This compound has shown excellent activity in vitro and in vivo, with antitumor efficacy in both s.c. and orthotopic xenograft tumor models when administered i.v. The structure-activity relationships and the in vitro and in vivo activity of analogs in this series are described.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Synthetic Route of 20744-39-2.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Abdelaziz, Ahmed M.; Basnet, Sunita K. C.; Islam, Saiful; Li, Manjun; Tadesse, Solomon; Albrecht, Hugo; Gerber, Cobus; Yu, Mingfeng; Wang, Shudong published the artcile< Synthesis and evaluation of 2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione derivatives as Mnk inhibitors>, Electric Literature of 20744-39-2, the main research area is spiro cyclohexane imidazopyridine dione preparation chemoselective antitumor Mnk inhibitor; Anti-cancer; Inhibitor; Mnk; eFT508; eIF4E.

A series of 2’H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione derivatives I (R = pyridin-4-yl, pyrimidin-4-yl, oxazol-2-yl, etc.) is presented as Mnk inhibitors. Some of them showed sub-micromolar to low nanomolar inhibitory activities against Mnk1/2 with a high level of selectivity for both kinases over CDKs. Biochem. assays revealed that compounds I (R = pyridin-4-yl, pyrimidin-4-yl) are non-ATP-competitive inhibitors of Mnks. Lead compound I (R = pyrimidin-4-yl) demonstrated a high selectivity for Mnk1/2 over a selection of 51 kinases, and displayed anti-proliferative activities against a panel of cancer cell lines. However, this compound in combination with our inhouse CDK4/6 inhibitor 83 did not show a synergistic effect in A2780 ovarian cancer cells, suggesting that caution be exercised in the selection of an agent to be combined with an Mnk inhibitor.

Bioorganic & Medicinal Chemistry Letters published new progress about Antitumor agents. 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Electric Literature of 20744-39-2.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Yu, Jianjun; Xu, Lei; Hong, Duidui; Zhang, Xiaotuan; Liu, Jieyu; Li, Daqiang; Li, Jia; Zhou, Yubo; Liu, Tao published the artcile< Design, synthesis, and biological evaluation of novel phenol ether derivatives as non-covalent proteasome inhibitors>, Related Products of 20744-39-2, the main research area is phenol ether preparation proteasome inhibitor antitumor SAR mol docking; Non-covalent; Non-peptide; Phenol ether; Proteasome inhibitor; Solid cancers.

A series of novel phenol ether derivatives I (n = 1, 2; R1 = Me, methoxy, n-Pr, etc.; R2 = 4-FC6H4, 2-naphthyl, 3-pyridinyl, etc.) were designed, synthesized, and evaluated as non-covalent proteasome inhibitors. Most compounds exhibited moderate to excellent proteasome inhibitory activity. In particular, compound I (n = 1; R1 = n-Bu; R2 = pyridazine-4-yl) proved to be the most potent compound (chymotrypsin-like: IC50 = 49 nM), exhibiting a 2-fold higher potency compared to the reported PI-1840. Besides, compound I (n = 1; R1 = n-Bu; R2 = pyridazine-4-yl) exhibited excellent metabolic stability and selective anti-proliferative activity against solid cancer cell lines including HepG2 and HGC27, providing incentive for the further development as a potential anticancer agent against solid cancers.

European Journal of Medicinal Chemistry published new progress about Amines Role: RCT (Reactant), RACT (Reactant or Reagent). 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Related Products of 20744-39-2.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Gumus, Selcuk published the artcile< A computational study on substituted diazabenzenes>, Reference of 20744-39-2, the main research area is aromaticity diazabenzene substituent effect.

The results of computational calculations on the aromaticity of the monosubstituted diazabenzenes (pyridazine, pyrimidine, and pyrazine) are reported herein. The aromaticity of the parent heterocycle was enhanced by substitution of strong electron-withdrawing groups. The effects of the position of the substituent on the aromaticity and the stability of the system were also studied by studying all possible derivatives of the systems.

Turkish Journal of Chemistry published new progress about Aromaticity. 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Reference of 20744-39-2.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Ren, Huiyu; Bakas, Nicole A.; Vamos, Mitchell; Chaikuad, Apirat; Limpert, Allison S.; Wimer, Carina D.; Brun, Sonja N.; Lambert, Lester J.; Tautz, Lutz; Celeridad, Maria; Sheffler, Douglas J.; Knapp, Stefan; Shaw, Reuben J.; Cosford, Nicholas D. P. published the artcile< Design, Synthesis, and Characterization of an Orally Active Dual-Specific ULK1/2 Autophagy Inhibitor that Synergizes with the PARP Inhibitor Olaparib for the Treatment of Triple-Negative Breast Cancer>, Computed Properties of 20744-39-2, the main research area is pyrimidine synthesis anticancer ULK1 ULK2 PARP breast cancer autophagy.

Inhibition of autophagy, the major cellular recycling pathway in mammalian cells, is a promising strategy for the treatment of triple-neg. breast cancer (TNBC). We previously reported SBI-0206965, a small mol. inhibitor of unc-51-like autophagy activating kinase 1 (ULK1), which is a key regulator of autophagy initiation. Herein, we describe the design, synthesis, and characterization of new dual inhibitors of ULK1 and ULK2 (ULK1/2). One inhibitor, SBP-7455 (compound 26), displayed improved binding affinity for ULK1/2 compared with SBI-0206965, potently inhibited ULK1/2 enzymic activity in vitro and in cells, reduced the viability of TNBC cells and had oral bioavailability in mice. SBP-7455 inhibited starvation-induced autophagic flux in TNBC cells that were dependent on autophagy for survival and displayed synergistic cytotoxicity with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib against TNBC cells. These data suggest that combining ULK1/2 and PARP inhibition may have clin. utility for the treatment of TNBC.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Computed Properties of 20744-39-2.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Ding, Xiao; Stasi, Luigi Piero; Dai, Xuedong; Long, Kai; Peng, Cheng; Zhao, Baowei; Wang, Hailong; Sun, Changhui; Hu, Huan; Wan, Zehong; Jandu, Karamjit S.; Philps, Oliver J.; Chen, Yan; Wang, Lizhen; Liu, Qian; Edge, Colin; Li, Yi; Dong, Kelly; Guan, Xiaoming; Tattersall, F. David; Reith, Alastair D.; Ren, Feng published the artcile< 5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy>, Formula: C4H5N3, the main research area is CNS penetration LRRK2 Parkinson’s disease PFI unbound fraction; CNS penetration; LRRK2; PFI; Parkinson’s disease; Unbound fraction.

We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18, 2-(benzyloxy)-5-morpholino-N-(pyridazin-4-yl)benzamide [2305380-32-7], proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following i.v. infusion at 5 mg/kg/h.

Bioorganic & Medicinal Chemistry Letters published new progress about Central nervous system. 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Formula: C4H5N3.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Zhang, Hai-xiang; Hong, Dong-feng; Chen, Cheng-liang published the artcile< Synthesis of 4-aminopyridazine>, Category: pyridazine, the main research area is dichloro amino pyridazine amino synthesis yield.

The starting material 3,6-dichloropyridazine reacted with chlorine to produce 3,4,6-trichloropyridazine, then followed with methanol and ammonia to synthesize 3,6-dichloro-4-aminopyridazine, which via catalytic dechlorination reaction achieved object compound 4-amino pyridazine and gave a 48.2% overall molar yield. Its structure was analyzed and characterized through m.p. testing, 1H NMR and mass spectrometry.

Yingyong Huagong published new progress about 20744-39-2. 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Category: pyridazine.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Garcia-Carceles, Javier; Decara, Juan M.; Vazquez-Villa, Henar; Rodriguez, Ramon; Codesido, Eva; Cruces, Jacobo; Brea, Jose; Loza, Maria I.; Alen, Francisco; Botta, Joaquin; McCormick, Peter J.; Ballesteros, Juan A.; Benhamu, Bellinda; Rodriguez de Fonseca, Fernando; Lopez-Rodriguez, Maria L. published the artcile< A Positive Allosteric Modulator of the Serotonin 5-HT2C Receptor for Obesity>, Product Details of C4H5N3, the main research area is anorectic serotonin receptor modulator preparation obesity benzylindolyl methylpyridinamine.

The 5-HT2CR agonist lorcaserin, clin. approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT2CR allosteric modulators as safer antiobesity drugs, a chem. library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogs 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands. PAM 11 was very active in feeding inhibition in rodents, an effect that was not related to the activation of 5-HT2AR. A combination of 11 with the SSRI sertraline increased the anorectic effect. Subchronic administration of 11 reduced food intake and body weight gain without causing CNS-related malaise. The behavior of compound 11 identified in this work supports the interest of a serotonin 5-HT2CR PAM as a promising therapeutic approach for obesity.

Journal of Medicinal Chemistry published new progress about 5-HT2C receptors Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Product Details of C4H5N3.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Chen, Ying-Chu; Faver, John C.; Ku, Angela F.; Miklossy, Gabriella; Riehle, Kevin; Bohren, Kurt M.; Ucisik, Melek N.; Matzuk, Martin M.; Yu, Zhifeng; Simmons, Nicholas published the artcile< C-N Coupling of DNA-Conjugated (Hetero)aryl Bromides and Chlorides for DNA-Encoded Chemical Library Synthesis>, Related Products of 20744-39-2, the main research area is DNA encoded heteroaryl amide library synthesis.

DNA-encoded chem. library (DECL) screens are a rapid and economical tool to identify chem. starting points for drug discovery. As a robust transformation for drug discovery, palladium-catalyzed C-N coupling is a valuable synthetic method for the construction of DECL chem. matter; however, currently disclosed methods have only been demonstrated on DNA-attached (hetero)aromatic iodide and bromide electrophiles. We developed conditions utilizing an N-heterocyclic carbene-palladium catalyst that extends this reaction to the coupling of DNA-conjugated (hetero)aromatic chlorides with (hetero)aromatic and select aliphatic amine nucleophiles. In addition, we evaluated steric and electronic effects within this catalyst series, carried out a large substrate scope study on two representative (hetero)aryl bromides, and applied this newly developed method within the construction of a 63 million-membered DECL.

Bioconjugate Chemistry published new progress about Anilines Role: CMB (Combinatorial Study), RCT (Reactant), RACT (Reactant or Reagent). 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Related Products of 20744-39-2.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Kuraishi, Tsukasa published the artcile< Synthesis of 4-aminopyridazine>, Name: Pyridazin-4-amine, the main research area is PYRIDINES/preparation of.

3,4,6-Trichloropyridazine (20 g.) heated 5 hrs. in a sealed tube in an oil bath at 100-5° with absolute EtOH saturated with NH3 and the solvent removed in vacuo yielded 7 g. 4-amino-3,6-dichloropyridazine (I), m. 203° (from H2O). This (2 g.) in 30 cc. MeOH containing 1 g. NaOH catalytically hydrogenated (Pd-C), the solvent distilled, and the residue extracted with AcOEt yielded 1 g. 4-aminopyridazine (II), m. 129-31. Absorption maximum in EtOH were: II, 252 and 281 mμ (ε 11,350 and 3,690); 3-aminopyridazine (Steck, et al., C.A. 49, 8987h), 234 and 301-2 mμ (ε 9.200 and 2,400); and I, 256 and 294-5 mμ (ε 9,800 and 4,500).

Pharmaceutical Bulletin published new progress about UV and visible spectra. 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Name: Pyridazin-4-amine.

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem