The Saga of Thalidomide

Mellin, Gilbert W.; Katzenstein, Michael

doi:10.1056/nejm196212062672305

Cited by 238 publications

(38 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In some cases, severe side effects have been reported for one enantiomer, whereas the other enantiomer has a favorable benefit-risk profile and is regarded a valuable drug (e.g. penicillamine [1], thalidomide [2]). Even if most of the side effects of enantiomers are usually tolerable, the compounds have to be metabolized nevertheless and thus represent an unnecessary burden.…”

Section: Introductionmentioning

confidence: 99%

Strategies in method development to quantify enantiomeric impurities using CE

2008

View full text Add to dashboard Cite

The growing number of chiral new drug substances requires increasing efforts in developing enantioselective methods. According to International conference on Harmonization guidelines, one should quantify the enantiomeric impurity of 0.1% relative to the major constituent. Capillary electrophoresis has evolved into an important tool for the separation of chiral drugs. The common strategies consist of two steps: firstly, initial separation conditions are evaluated. This screening usually focuses on the selection of the appropriate chiral selector. In our study 22 neutral, anionic or cationic cyclodextrins were dissolved in phosphate buffer (pH 2.5, 50 mM, CD conc.: 2.0%). Then they were investigated for the separation of 14 chiral compounds. Secondly, the obtained initial conditions for the enantiomeric separation were optimized in terms of resolution and analysis time. In our approach, important optimized factors including the concentration of the chiral selector (1-10%), the pH of the buffer (2.0-9.0), and the percentage of organic modifier (0-15%) were studied. This common strategy was completed by elaborating final requirements for the quantification of the enantiomeric impurity. A resolution between 3 and 4 was found to be necessary for the racemic mixture during the screening and optimization steps, in order to later allow for peak overloading and thus to sufficiently increase the signal-to-noise ratio. The complete strategy was conducted for atenolol, isoprenaline, verapamil and mandelic acid.

show abstract

Section: Introductionmentioning

confidence: 99%

Strategies in method development to quantify enantiomeric impurities using CE

2008

View full text Add to dashboard Cite

show abstract

“…Thalidomide [N(α)-phthalimidoglutarimide] has a long pharmacological history, having been used as a sedative, an antiinflammatory, and an immunosuppressive agent (Mellin et al 1962). The idea of an outright immunosuppression by THD was rightly rejected .…”

Section: Introductionmentioning

confidence: 99%

Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and transmigration of cytokine- and endotoxin-activated endothelium

Dunzendorfer¹,

Schratzberger²,

Reinisch³

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

Vascular endothelium activated by endotoxin and cytokines plays an important role in organ inflammation and blood leukocyte recruitment. Neutrophils, which are a homogeneous population of effector cells, are rapidly attracted in large numbers to sites of inflammation where they form an early response to infection or injury. Excessive production of various interleukins, TNF, arachidonic acid metabolites, and other substances by neutrophils and macrophages results in systemic endothelial cell injury, a fundamental problem. In the present study, we investigated in vitro the effects of thalidomide (THD) on activation of endothelial cells for enhanced transmigration of neutrophils by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF), and interleukin-1 (IL-1). Modulation of endotoxin- and cytokine-induced neutrophil chemotaxis and respiratory burst by THD were also studied. Treatment of HUVEC with THD in combination with LPS, TNF, and IL-1, respectively, antagonized LPS-activated transmigration of neutrophils but stimulated the effects of TNF and IL-1. All of the agents used-THD, LPS, TNF, and IL-1-inhibited neutrophil chemotaxis. Addition of THD to the neutrophils had no effect on LPS-inhibited chemotaxis whereas the TNF- and IL-1-induced chemotaxis was modulated in a bimodal manner. However, THD failed to influence neutrophil respiratory burst activity. Results demonstrate that THD differentially affects mediator-induced activation of HUVEC and neutrophils.

show abstract

“…Consequently, it might exhibit parallel physiological effects and enhanced subtype selectivity due to similar interactions in the lipophilic binding pocket (L2, see Figure S1 in Supplementary material for the model). 22 Moreover, metabolism by liver microsomes would be expected to be different for a cyclopropyl substituent as compared to an ethynyl functional group. Hence, the C(8)-substituted cyclopropyl analog GL-I-78 (3) was prepared based on this hypothesis.…”

Section: Resultsmentioning

confidence: 99%

“…This process gave methyl oxadiazole GL-I-65 (9a), ethyl oxadiazole GL-I-66 (9b) and isopropyl oxadiazole GL-I-81 (9c) in improved yields of 79-85%, respectively, as depicted in Scheme 5. To explore the extent of flexibility of the hydrogen-bond acceptor in the binding pocket designed H1 in the pharmacophore/receptor model (see Figure S1 in Supplementary material), 22,36 it was decided to synthesize a linear nitrile at the C(3) position, which has sometimes been employed to increase water solubility of a ligand and has also been used to reduce possible oxidative metabolism by the liver in clinical studies. 45 The nitrile MP-III-018.A (10) The characterization of the lead compound 2 was being carried out simultaneously with the synthesis and assessment of the novel analogs.…”

mentioning

confidence: 99%

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

Li¹,

Rajesh²,

Kodali³

et al. 2018

Arkivoc

View full text Add to dashboard Cite

A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F-S-CH 3 (2), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reverses PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral (S)-CH 3 ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the labile ester functionality in 2 to improve the metabolic stability, cytotoxicity, and activity as compared to 2. Based on the data to date, the most promising ligands are the N-cyclopropyl amide GL-I-55 (8c) and the methyl bioisostere GL-I-65 (9a). The in vitro metabolic stability, cytotoxicity and in vivo locomotor effects are described in this report. Based on these results, 8c and 9a are the most promising for further in vivo pharmacology.

show abstract

The Saga of Thalidomide

Cited by 238 publications

References 31 publications

Strategies in method development to quantify enantiomeric impurities using CE

Strategies in method development to quantify enantiomeric impurities using CE

Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and transmigration of cytokine- and endotoxin-activated endothelium

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

Contact Info

Product

Resources

About