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ISOXAZOLE DERIVATIVES

The present invention is concerned with novel isoxazole derivatives of formula (I), wherein X, R1, R2, R3, R4 and R5 are as described herein, as well as pharmaceutically acceptable salts and esters thereof. The active compounds of the present invention have affinity and selectivity for GABA A alpha5 receptor. Further the present invention is concerned with the manufacture of the active compounds of formula I, pharmaceutical compositions containing them and their use as medicaments

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1360 – PubChem

 

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Peptide nucleic acid monomers and oligomers

Novel peptide nucleic acid (PNA) oligomers and their constituent monomers are disclosed. The PNA oligomers and linked PNAs form triple stranded structures with nucleic acids that show an increased specificity for thymidine in nucleic acid targets relative to naturally occurring nucleobases.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1478 – PubChem

 

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Pharmacokinetic optimization of class-selective histone deacetylase inhibitors and identification of associated candidate predictive biomarkers of hepatocellular carcinoma tumor response

Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead 5 (HDAC1 IC50 = 60 nM, mouse CL = 39 mL/min/kg, mouse F = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h¡¤ng/mL). We then evaluated 5 in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1960 – PubChem

 

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In heterogeneous catalysis, the catalyst is in a different phase from the reactants. Recommanded Product: 141-30-0, At least one of the reactants interacts with the solid surface in a physical process called adsorption in such a way. 141-30-0, name is 3,6-Dichloropyridazine. In an article£¬Which mentioned a new discovery about 141-30-0

FUSED HETEROCYCLIC 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE I INHIBITORS

Novel compounds are provided which are 1 1 -beta-hydroxysteroid dehydrogenase type I inhibitors. 1 1-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 1 1-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds have the structure: W-L-Z or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein W, L are defined herein and Z is selected from the following bicyclic heteroaryl groups: (a), (b), (c), (d).

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1419 – PubChem

 

The important role of 3,6-Dichloropyridazine

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An electrochemical nickel-catalyzed arylation of 3-amino-6- chloropyridazines

3-Amino-6-aryl- and 3-amino-6-heteroarylpyridazines have been obtained in generally good yield using a nickel-catalyzed electrochemical cross-coupling between 3-amino-6-chloropyridazines and aryl or heteroaryl halides at room temperature. Comparative experiments involving classical palladium-catalyzed reactions, such as Suzuki, Stille, or Negishi cross-couplings, reveal that the electrochemical method can constitute a reliable alternative tool for biaryl formation. A possible reaction mechanism is proposed on the basis of electrochemical analyses.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1895 – PubChem

 

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Related Products of 141-30-0, The reaction rate of a catalyzed reaction is faster than the reaction rate of the uncatalyzed reaction at the same temperature.141-30-0, Name is 3,6-Dichloropyridazine, molecular formula is C4H2Cl2N2. In a Article£¬once mentioned of 141-30-0

Cinnamonitrile adjuvants restore susceptibility to beta-lactams against methicillin-resistant staphylococcus aureus

beta-Lactams are used routinely to treat Staphylococcus aureus infections. However, the emergence of methicillin-resistant S. aureus (MRSA) renders them clinically precarious. We describe a class of cinnamonitrile adjuvants that restore the activity of oxacillin (a penicillin member of the beta-lactams) against MRSA. The lead adjuvants were tested against six important strains of MRSA, one vancomycin-intermediate S. aureus (VISA) strain, and one linezolid-resistant S. aureus strain. Five compounds out of 84 total compounds showed broad potentiation. At 8 muM (E)-3-(5-(3,4-dichlorobenzyl)-2-(trifluoromethoxy)phenyl)-2-(methylsulfonyl)acrylonitrile (26) potentiated oxacillin with a >4000-fold reduction of its MIC (from 256 to 0.06 mg¡¤L-1). This class of adjuvants holds promise for reversal of the resistance phenotype of MRSA.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1901 – PubChem

 

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Preparation of Heteroaryl Phenylmethanes and a 13C and 15N NMR Spectroscopic Study of their Conjugate Carbanions. Rotational Isomerism and Charge Maps of the Anions and Ranking of the Charge Demands of the Heterocycles

2-Benzylpyridazine, 4-benzylpyrimidine, 2-benzylpyrimidine and 2-benzylpyrazine, (5-8) have been prepared in order to study their 13C and 15N spectra and those of their conjugate carbanions (1-4).These systems are aza-homologues of the previously reported benzylpyridines and have been considered to evaluate the effect of aza-substitution upon rotational isomerism and charge maps in the anions.Two synthetic approaches have been followed: (i) decarboxylation of alpha-(heteroaryl)phenylacetic acids, in turn obtained by nucleophilic substitution of phenylacetonitrile anion on the pertinent halogenoazine (or a correspondingly available derivative); (ii) by nucleophilic substitution of benzyl(tributylphosphinium)ylide on the pertinent halogenoazine.The 13C and 15N NMR data for 1-4 indicate that, at room temperature, there is slow rotation about the bond between the carbanionic carbon and the carbon atom of the heterocycle: this generates geometrical isomerism in the anions 1-4.The NMR date are treated with the ?-charge-shift equations (1)-(4) to obtain the local variations of the ?-electron density.By evaluating, in anions 1-4, the fraction of ?-charge transferred to the heterocycle from the carbanionic carbon it is possible to obtain the charge demands, cx of the heterocycles, and thus rank them on the same scale as primary organic functionalities.It is found that the 4-pyrimidyl is the strongest electron-withdrawing heterocyclic residue, comparable with the acetyl group.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1581 – PubChem

 

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ANTAGONISTS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4

Disclosed herein are 3-azabicyclo[3.1.0]hexan-6-amine compounds, which may be useful as antagonists of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1432 – PubChem

 

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Pyridazine-derived gamma-secretase modulators

SAR of a novel series of pyridazine-derived gamma-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42 and Abeta40, and maintain the levels of total Abeta. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.

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Syntheses and structure-activity relationship (SAR) studies of 2,5-diazabicyclo[2.2.1]heptanes as novel alpha7 neuronal nicotinic receptor (NNR) ligands

Biaryl substituted 2,5-diazabicyclo[2.2.1]heptanes have been synthesized and tested for their affinity toward alpha7 neuronal nicotinic receptors (NNRs). SAR studies established that 5-N-methyl substituent, heteroaryl linker and the nature of terminal aryl group are critical for the ligand to achieve potent alpha7 NNR agonist activity.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N1788 – PubChem