3506-36-3Relevant articles and documents
Derivatization of common antidepressant drugs increases inhibition of acid sphingomyelinase and reduces induction of phospholipidosis
Rhein, Cosima,L?ber, Stefan,Gmeiner, Peter,Gulbins, Erich,Tripal, Philipp,Kornhuber, Johannes
, p. 1837 - 1845 (2018)
In recent studies, major depressive disorder (MDD) was linked to an increase in acid sphingomyelinase (ASM) activity. Several drugs that are commonly used to treat MDD functionally inhibit the lysosomal enzyme ASM and are called functional inhibitors of ASM (FIASMAs). These drugs are classified as cationic amphiphilic drugs (CADs) that influence the catalytic activities of different lysosomal enzymes. This action results in the side effect of phospholipidosis (PLD), which describes a detrimental increase in the phospholipid content in lysosomes. FIASMAs differ only slightly in their physico-chemical properties, but their effects on ASM activity and induction of the lysosomal phospholipid content vary significantly. In this study, we systematically induced minor chemical modifications to the FIASMAs imipramine, desipramine and fluoxetine. We generated a library of 45 new CADs with slightly different log P (logarithmic partition coefficient) and pKa (logarithmic acid dissociation constant) values. The effects of the compounds on the ASM activity and lysosomal phospholipid content were assessed in cell culture assays. We identified four compounds with beneficial effects, i.e., increased ASM activity inhibition and reduced PLD induction compared with the original drugs. The compounds HT04, RH272B and RH272D outperformed the original imipramine, whereas RH281A performed better than desipramine. Thus, minor chemical variations of CADs impact lysosomal metabolism in a specific manner and can lead to antidepressant drugs with less deleterious side effects.
SMALL MOLECULE CMKLR1 ANTAGONISTS IN INFLAMMATORY DISEASE
-
Paragraph 0199; 0230; 0232; 0241, (2020/12/01)
α-NETA analogs are provided for the treatment of inflammatory disease.
Remote C(sp3)-H Oxygenation of Protonated Aliphatic Amines with Potassium Persulfate
Lee, Melissa,Sanford, Melanie S.
supporting information, p. 572 - 575 (2017/02/10)
This letter describes the development of a method for selective remote C(sp3)-H oxygenation of protonated aliphatic amines using aqueous potassium persulfate. Protonation serves to deactivate the proximal C(sp3)-H bonds of the amine substrates and also renders the amines soluble in the aqueous medium. These reactions proceed under relatively mild conditions (within 2 h at 80 °C with amine as limiting reagent) and do not require a transition metal catalyst. This method is applicable to a variety of types of C(sp3)-H bonds, including 3°, 2°, and benzylic C-H sites in primary, secondary, and tertiary amine substrates.