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Necroptosis, a form of programmed cell death, plays a critical role in various diseases, including inflammato-ry, infectious and degenerative diseases. We previously identified TAK-632 (6) as a potent inhibitor of necrop-tosis by targeting both RIPK1 and RIPK3 kinases. Herein, we performed three rounds of structural optimizations of TAK-632 and elucidated structure-activity relationships to generate more potent inhibitors by targeting RIPK3. The analogues with carbamide groups exhibited great anti-necroptotic activities and compound 42 showed >60-fold selectivity for RIPK3 than RIPK1. It blocked necrosome formation by specifically inhibiting the phosphorylation of RIPK3 in necroptotic cells. In a TNF-induced systemic inflammatory response syn-drome model, it significantly protected mice from hypothermia and death at a dose of 5 mg/kg, which was much more effective than TAK-632. Moreover, it showed favorable and drug-like pharmacokinetic properties in rats with an oral bioavailability of 25.2%. Thus, these RIPK3-targeting small molecules represent promising lead structures for further development.
This article was published in the following journal.
Name: Journal of medicinal chemistry
A visible-light-promoted redox neutral γ,γ-difluoroallylation of cycloketone oxime ethers with trifluoromethyl alkenes through C-C and C-F bond cleavage has been achieved, which affords various cyan...
Aiming to balance the injection and transport of electrons and holes, nitrogen heterocycle and 1,3,4-oxadiazole derivatives were introduced in iridium(iii) complexes to obtain organic light-emitting d...
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To investigate the efficacy of laser therapy associated with fluorotherapy in the desensibitization of hypomineralized teeth in children 8 to 12 years of age. A randomized blinded clinical...
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A dual inhibitor of both cyclooxygenase and lipoxygenase pathways. It exerts an anti-inflammatory effect by inhibiting the formation of prostaglandins and leukotrienes. The drug also enhances pulmonary hypoxic vasoconstriction and has a protective effect after myocardial ischemia.
A dihydropyridine derivative, which, in contrast to NIFEDIPINE, functions as a calcium channel agonist. The compound facilitates Ca2+ influx through partially activated voltage-dependent Ca2+ channels, thereby causing vasoconstrictor and positive inotropic effects. It is used primarily as a research tool.
Derivatives of benzophenone (with the structural formula phenyl-(C=O)-phenyl).
An anti-inflammatory 9-fluoro-glucocorticoid.
Compounds based on a propanolamine attached via an OXYGEN atom to a phenoxy ring. The side chain is one carbon longer than PHENYLETHYLAMINES.
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