Glucocorticoids are among the most common therapeutic agents used in medical practice, yet their mechanisms of action are only partly understood. This review summarizes our understanding of how glu...

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Antiinflammatory Action of Glucocorticoids — New Mechanisms for Old Drugs

Fluorine in medicinal chemistry: A review of anti-cancer agents

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)60326-3.pdf

Glucocorticoid resistance in inflammatory diseases

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras

Inhibitors of farnesyl protein transferase

Topical corticosteroids were introduced into medicine about 50 years ago. They represent a significant milestone in dermatologic therapy. Despite encouragement to report observed adverse drug reactions, the clinical practice of reporting is poor and incomplete. Likewise, adverse effects and safety of topical corticosteroids are neglected in the medical literature. The authors provide an updated review of their adverse-effect profile. Children are more prone to the development of systemic reactions to topically applied medication because of their higher ratio of total body surface area to body weight. Cutaneous adverse effects occur regularly with prolonged treatment and are dependent on the chemical nature of the drug, the vehicle, and the location of its application. The most frequent adverse effects include atrophy, striae, rosacea, perioral dermatitis, acne, and purpura. Those that occur with lower frequency include hypertrichosis, pigmentation alterations, delayed wound healing, and exacerbation of skin infections. Of particular interest is the rate of contact sensitization against corticosteroids, which is considerably higher than generally believed. Systemic reactions such as hyperglycemia, glaucoma, and adrenal insufficiency have also been reported to follow topical application. The authors provide an updated review of local and systemic adverse effects upon administration of topical corticosteroids, including the latest FDA report on the safety of such steroids in children. Learning objective At the completion of this learning activity, participants should be familiar with topical corticosteroids and their proper use.

https://www.jaad.org/article/S0190-9622(05)00255-0/pdf

Adverse Effects of Topical Glucocorticosteroids

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior side-effect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.

https://www.pnas.org/content/pnas/101/1/227.full.pdf

Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

Silylierte 2-Thiouracile reagieren mit acylierten Halogenzuckern in Gegenwart von Silberperchlorat in Benzol in hohen Ausbeuten zu den acylierten 2-Thiopyrimidin-nucleosiden. Analog werden 2-Thiocytidin und 2-Thiouridin-5-essigsaure-methylester, zwei seltene Nucleoside aus t-RNA, dargestellt. Der Mechanismus der Reaktion wird diskutiert.



Syntheses of Nucleosides, VII. A New Synthesis of 2-Thiopyrimidine Nucleosides



Silylated 2-thiouracils react with acylated 1-halosugars in the presence of silver perchlorate in benzene to give the acylated 2-thiopyrimidine nucleosides in high yields. 2-Thiocytidine and methyl 2-thiouridine-5-acetate, two rare nucleosides from t-RNA, are prepared analogously. The mechanism of the reaction is discussed.

Nucleosidsynthesen, VII. Eine einfache Synthese von 2-Thiopyrimidin-nucleosiden

The invention relates to non-steroidal gestagens of general formula (I), wherein R?1 and R2? are the same or different and stand for a hydrogen atom, a C?1?-C5 alkyl group or a halogen atom, or together with the C atom of the chain stand for a ring with 3-7 units, R?3? means a C?1?-C5 alkyl group or a partially or fully fluorinated C1-C5 alkyl group, A stands for an optionally substituted mono or bi-cyclic aromatic ring, an ester group -COOR?4?, an alkenyl group -CR5=CR6R7, an alkinyl group -C CR5 or for a partially or fully fluorinated C?1?-C5 alkyl group, B means a carbonyl group or a CH2 group and Ar is a ring system selected from the group of general partial formulae (2-11). When B represents a CH2 group in general formula (I), Ar additionally means a phenyl radical of partial general formula (12). The novel compounds display a very strong affinity to the gestagen receptor. They can be used on their own or in combination with oestrogen's in contraceptive preparations. They can also be used in the treatment of endometriosis. They can be used with oestrogen's in preparations for the treatment of gynaecological disorders. They can also be used to treat pre-menstrual complaints and in substitution therapy. Their androgen activity enables them to be used for male fertility control, male HRT and to treat andrological syndromes.

Nonsteroidal (hetero) cyclically-substituted acylanilides with mixed gestagenic and androgenic activity

The invention relates to compounds of general formula (I) and the use thereof for producing medicaments that are utilized for treating and preventing diseases which are accompanied by inflammatory, allergic, and/or proliferative processes.

Non-steroidal anti-inflammatory agents

This invention describes the use of the compounds of general formula I in which A, B, A, Ar, R 1 , R 2 and R 3 have the meaning that is indicated in more detail in the description, for the production of pharmaceutical agents with anti-inflammatory action. The compounds of general formula I show a clear dissociation between anti-inflammatory and metabolic action.

Peter Strehlke

Papers

Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

Nucleosidsynthesen, VII. Eine einfache Synthese von 2-Thiopyrimidin-nucleosiden

Nonsteroidal (hetero) cyclically-substituted acylanilides with mixed gestagenic and androgenic activity

Non-steroidal anti-inflammatory agents

Nonsteroidal anti-inflammatory agents