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Compounds that react irreversibly with cysteines have reemerged as potent and selective tools for altering protein function, serving as chemical probes and even clinically approved drugs. The exquisite sensitivity of human immune cell signaling pathways to oxidative stress indicates the likely, yet still underexploited, general utility of covalent probes for selective chemical immunomodulation. Here, we provide an overview of immunomodulatory cysteines, including identification of electrophilic compounds available to label these residues. We focus our discussion on three protein classes essential for cell signaling, which span the ?druggability? spectrum from amenable to chemical probes (kinases), somewhat druggable (proteases), to inaccessible (phosphatases). Using existing inhibitors as a guide, we identify general strategies to guide the development of covalent probes for selected undruggable classes of proteins and propose the application of such compounds to alter immune cell functions.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N186 – PubChem

 

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The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N188 – PubChem

 

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Compounds of formula (I), pharmaceutical formulations thereof and the use of such compounds for treating endothelin mediated diseases or conditions are described herein. 1 The compounds of the present invention have affinity for endothelin receptors, are selective for ETA over ETB, and thus are useful in the treatment of conditions mediated by endothelin.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N175 – PubChem

 

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Despite many efforts, one of the smallest heterocycles containing two nitrogen atoms, pyridazine, could not be converted to its N,N-dioxide (see, however, Nakadate et al. Chem. Pharm. Bull. 1970, 18, 1211-1218). HOF·CH3CN, made easily from diluted fluorine, was able to accomplish this task in a fast reaction with good yields.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N199 – PubChem

 

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Novel compounds of structural formula (I) are disclosed. As modulators of the Cannabinoid-1 (CB1) receptor, these compounds are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. As such, compounds of the present invention are useful as in the treatment, prevention and suppression of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders (e.g., multiple sclerosis, Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis), cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson’s disease, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.

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Novel imidazoline derivatives were discovered to be potent neuropeptide Y Y5 receptor antagonists. High-throughput screening of Merck sample collections against the human Y5 receptor resulted in the identification of 2,4,4-triphenylimidazoline (1), which had an IC50 of 54 nM. Subsequent optimization led to the identification of several potent derivatives.

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Pyridazine – Wikipedia,
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The present invention relates to substituted 4-hydroxypyrimidine-5-carboxamides useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.

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The present invention relates to substituted pyrimidines useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.

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Pyridazine – Wikipedia,
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Bis(allyl)-ruthenium(IV) complexes with phosphinous acid ligands as catalysts for nitrile hydration reactions

Several mononuclear ruthenium(iv) complexes with phosphinous acid ligands [RuCl2(eta3:eta3-C10H16)(PR2OH)] have been synthesized (78-86% yield) by treatment of the dimeric precursor [{RuCl(mu-Cl)(eta3:eta3-C10H16)}2] (C10H16 = 2,7-dimethylocta-2,6-diene-1,8-diyl) with 2 equivalents of different aromatic, heteroaromatic and aliphatic secondary phosphine oxides R2P(O)H. The compounds [RuCl2(eta3:eta3-C10H16)(PR2OH)] could also be prepared, in similar yields, by hydrolysis of the P-Cl bond in the corresponding chlorophosphine-Ru(iv) derivatives [RuCl2(eta3:eta3-C10H16)(PR2Cl)]. In addition to NMR and IR data, the X-ray crystal structures of representative examples are discussed. Moreover, the catalytic behaviour of complexes [RuCl2(eta3:eta3-C10H16)(PR2OH)] has been investigated for the selective hydration of organonitriles in water. The best results were achieved with the complex [RuCl2(eta3:eta3-C10H16)(PMe2OH)], which proved to be active under mild conditions (60 C), with low metal loadings (1 mol%), and showing good functional group tolerance.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N201 – PubChem

 

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no abstract published

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Pyridazine – Wikipedia,
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