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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Thalidomide is metabolised almost exclusively by non-enzymatic hydrolysis. In plasma, unchanged thalidomide represents 80% of the circulatory components. Unchanged thalidomide was a minor component (<3% of the dose) in urine. In addition to thalidomide, hydrolytic products N-(o-carboxybenzoyl) glutarimide and phthaloyl isoglutamine formed via non-enzymatic processes are also present in plasma and in urine.
Barbiturate and Nonbarbiturate Sedative Hypnotic Intoxication
Published in Sam Kacew, Drug Toxicity and Metabolism in Pediatrics, 1990
S. Bertino Joseph, Michael D. Reed
Following oral administration of glutethimide, the drug is slowly and erratically absorbed.4 Ethanol increases the absorption of this agent dramatically.59 Due to its high lipid solubility, the drug rapidly concentrates in the brain and adipose tissue. Only a small amount of the drug is excreted in the urine (<2%), while the remainder of the drug is metabolized in the liver. While the average half-life is 5 to 22 h, half-lives averaging 40 h have been reported in intoxicated patients.60 To complicate matters, glutethimide is a racemic mixture, the D- and L-isomers of which follow dissimilar metabolic pathways. The D-isomer undergoes hydrolysis of the glutarimide ring with the subsequent formation of 4-hydroxy-2 ethyl-2 phenyl glutarimide (4HG). This metabolite is conjugated with glucuronic acid or is excreted unchanged. The L-isomer also is hydrolyzed with release of acetaldehyde and then glucuronidated. Other metabolites of each isomer may exist, although complete metabolic conversion remains to be described. While initial data with single doses suggested that 4HG possessed no pharmacologic activity in humans, other data suggest a correlation between the degree of toxicity and the 4HG serum concentration.60 To date, however, serum glutethimide and 4HG concentrations have found limited usefulness in directing the approach to the treatment of glutethimide intoxication.
Affinity Modification — Organic Chemistry
Published in Dmitri G. Knorre, Valentin V. Vlassov, Affinity Modification of Biopolymers, 1989
Dmitri G. Knorre, Valentin V. Vlassov
The possibility of such a reaction was demonstrated for the derivative of the antibiotic of the glutarimide family cycloheximide which interferes with protein biosynthesis on eukaryotic ribosomes. In model experiments when the derivative was irradiated in the presence of methylamine, it was found that substitution occurs predominantly at the meta position of the nitrophenyl grouping.138
Replacing the phthalimide core in thalidomide with benzotriazole
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mikhail Krasavin, Andrey Bubyrev, Alexander Kazantsev, Christopher Heim, Samuel Maiwald, Daniil Zhukovsky, Dmitry Dar’in, Marcus D. Hartmann, Alexander Bunev
The synthesis of the benzotriazole analogue 2 of thalidomide was achieved as detailed below. Commercially available glutarimide 3 was (dimethylamino)methylenated at the α-position using the Brederick’s reagent (4)8. The resulting derivative 5 readily entered the Regitz diazo transfer reaction9 with 4-nitrophenylsulfonyl azide (NsN3) to give hitherto undescribed 3-diazopiperidine-2,6-dione (6) in excellent yield. α-Diazocarbonyl compounds were recently established to regioselectively alkylate benzotriazoles at N2 when activated as Rh(II) carbenes10. Indeed, when α-diazoglutarimide (6) was activated by Rh(II) espionate (bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)]) (1 mol%) and reacted with benzotriazole, desired ‘benzotriazolo thalidomide’ 2 was obtained in excellent yield and complete regioselectivity (Scheme 1).
Ligands for cereblon: 2017–2021 patent overview
Published in Expert Opinion on Therapeutic Patents, 2022
Alexander Kazantsev, Mikhail Krasavin
The vast majority of CRBN ligands patented in 2017–2021 fall into a broadly defined category of ‘thalidomide-like,’ i. e. they either are outright modifications of thalidomide/lenalidomide/pomalidomide (classical IMiDs) or they are designed on the same principle, i. e. by linking the pharmacophoric glutarimide moiety to a heterocyclic replacement of phthalimide (thalidomide- and pomalidomide-like) or isoindolinone (lenalidomide-like). Very often (and patents by Dana-Farber Cancer Institute witness to that) the glutarimide moiety is presented as derivative of 3-aminoglutarimide decorated with various peripheral appendages. Such a strategy allowed them to identify degrons that they used directly in the PROTAC construction. A similar strategy was pursued by Kymera Therapeutics. However, in addition to a large number of newly substituted thalidomide- and lenalidomide-like building blocks Kymera also covered a large estate of (hetero)aromatics-fused glutarimides and even isosteres thereof. C4 Therapeutics was very inventive designing glutarimide moieties to various heteroaromatic moieties (mostly through a nitrogen atom) and proposing various isosteric replacements for glutarimide itself. This, however, did not preclude Kymera Therapeutics from finding a very nice niche and identifying tricyclic aromatic substituents for glutarimide that delivered very affine CRBN ligands.
Immunomodulators in newly diagnosed multiple myeloma: current and future concepts
Published in Expert Review of Hematology, 2021
Michel Delforge, Sophie Vlayen, Nicolas Kint
Thalidomide (alpha-N-[phtalimido]glutarimide) was introduced in the fifties of last century as a sedative and a drug for morning sickness during pregnancy. A few years later, it became clear that thalidomide use during pregnancy was associated with severe teratogenic malformations, affecting more than 10.000 infants worldwide, and therefore this drug was rapidly taken off the market [5]. Given its powerful in vitro immunomodulatory activities, thalidomide was further explored in several inflammatory diseases such as erythema nodusum leprosum and Behçet syndrome [6,7]. However, it was only three decades later that the clinical anti-myeloma activity of thalidomide was discovered. Eighty-four patients with refractory MM received thalidomide monotherapy in doses up to 800 mg per day with 32% responders [8]. This landmark study started a remarkable journey of thalidomide in the management of MM. However, despite the impressive clinical results, it became rapidly clear that the clinical development of thalidomide was hampered by its dark history of teratogenicity and its dose-limiting side effects such as sedation and most importantly peripheral neuropathy (PN). These observations stimulated the search for thalidomide derivatives with higher therapeutic efficacy and a more favorable toxicity profile. In that perspective, a series of amino-phtaloyl-substituted thalidomide analogues were generated with CC-5013 (lenalidomide or Revlimid®) and CC-4047 (pomalidomide or Imnovid®, formerly known as Actimid®) taken forward into clinical studies [9]. As will be discussed later on, lenalidomide and pomalidomide have currently outcompeted thalidomide largely in the management of MM.