Methylsulfamic acid esters. A new chemical class of oral antiarthritic agents

Walsh, David A.; Lo, Young S.; Shamblee, D. A.; Welstead, William J.; Nolan, Joseph C.; Graff, Gustav

doi:10.1021/jm00170a003

Cited by 6 publications

(7 citation statements)

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“…Among them, bisulfamates such as AHR-15010 65, were reported to possess anti-arthritic activity in adjuvant arthritis rats, acting by an unique mechanism of action. [141][142][143] It was suggested that this mechanism resulted from the inhibitory effect of AHR-15010 on CAs as it was demonstrated that these enzymes (and more specifically, isozyme CA II) are involved in bone resorption [2][3][4][5] (see also Table X, and the discussion on CA inhibitors in this review). The use of CAIs could be a valuable approach for the management of arthritic diseases, but no progress in this field has been registered ultimately.…”

Section: B Sulfamates As Anti-arthritis and Anti-osteoporosis Agentsmentioning

confidence: 99%

“…The arthritic diseases are systemic inflammatory diseases characterized by considerable damage of connective tissue structures of the joint and adjacent structures leading to progressive cartilage and bone destruction. [141][142][143] Diverse classes of therapeutic agents have been used over the past 40 years to treat arthritis including adrenal corticosteroids and non-steroidal anti-inflammatory drugs. [141][142][143] One of the clinical features of arthritis and also osteoporosis is bone resorption, leading to bone loss.…”

Section: B Sulfamates As Anti-arthritis and Anti-osteoporosis Agentsmentioning

confidence: 99%

“…[141][142][143] Diverse classes of therapeutic agents have been used over the past 40 years to treat arthritis including adrenal corticosteroids and non-steroidal anti-inflammatory drugs. [141][142][143] One of the clinical features of arthritis and also osteoporosis is bone resorption, leading to bone loss. [141][142][143] Development of compounds, which can act by inhibiting this phenomenon was reported to be beneficial for the treatment of these disorders.…”

Section: B Sulfamates As Anti-arthritis and Anti-osteoporosis Agentsmentioning

confidence: 99%

“…[141][142][143] One of the clinical features of arthritis and also osteoporosis is bone resorption, leading to bone loss. [141][142][143] Development of compounds, which can act by inhibiting this phenomenon was reported to be beneficial for the treatment of these disorders. Among them, bisulfamates such as AHR-15010 65, were reported to possess anti-arthritic activity in adjuvant arthritis rats, acting by an unique mechanism of action.…”

Section: B Sulfamates As Anti-arthritis and Anti-osteoporosis Agentsmentioning

confidence: 99%

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Sulfamates and their therapeutic potential

Winum¹,

Scozzafava²,

Montéro³

et al. 2004

Medicinal Research Reviews

196

153

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Starting from the very simple molecule sulfamic acid, O-substituted-, N-substituted-, or di-/tri-substituted sulfamates may be obtained, which show specific biological activities which were or started to be exploited for the design of many types of therapeutic agents. Among them, sulfamate inhibitors of aminoacyl-tRNA synthetases (aaRSs) were recently reported, constituting completely new classes of antibiotics, useful in the fight of drug-resistant infections. Anti-viral agents incorporating sulfamate moieties have also been obtained, with at least two types of such derivatives investigated: the nucleoside/nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitors, and the HIV protease inhibitors (PIs). In the increasing armamentarium of anti-cancer drugs, the sulfamates occupy a special position, with at least two important targets evidenced so far: the steroid sulfatases (STSs) and the carbonic anhydrases (CAs). An impressing number of inhibitors of STSs of the sulfamate type have been reported in the last years, with several compounds, such as 667COUMATE among others, progressing to clinical trials for the treatment of hormone-dependent tumors (breast and prostate cancers). This field is rapidly evolving, with many types of new inhibitors being constantly reported and designed in such a way as to increase their anti-tumor properties, and decrease undesired features (for example, estrogenicity, a problem encountered with the first generation such inhibitors, such as EMATE). Among the many isozymes of CAs, at least two, CA IX and CA XII, are highly overexpressed in tumors, being generally absent in the normal tissues. Inhibition of tumor-associated CAs was hypothesized to lead to novel therapeutic approaches for the treatment of cancer. Many sulfamates act as very potent (low nanomolar) CA inhibitors. The X-ray crystal structure of the best-studied isozyme, CA II, with three sulfamates (sulfamic acid, topiramate, and EMATE) has recently been reported, which allowed for a rationale drug design of new inhibitors. Indeed, low nanomolar CA IX inhibitors of the sulfamate type have been reported, although such compounds also act as efficient inhibitors of isozymes CA I and II, which are not associated with tumors. A large number of anti-convulsant sulfamates have been described, with one such compound, topiramate, being widely used clinically as anti-epileptic drug. By taking into consideration a side effect of topiramate, an anti-epileptic drug leading to weight loss in some patients, it has recently been proposed to use this drug and related sulfamates for the treatment of obesity. The rationale of this use is based on the inhibition of the mitochondrial CA isozyme, CA V, involved in lipogenesis. Some sulfamates were also shown to possess potent inhibitory activity against acyl coenzyme A:cholesterol acyltransferase, an enzyme involved in cholesterol metabolism. One such agent, avasimibe, is in advanced clinical trials for the treatment of hyperlipidemia and atherosclerosis. Thus, the sulfamate ...

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Section: B Sulfamates As Anti-arthritis and Anti-osteoporosis Agentsmentioning

confidence: 99%

Section: B Sulfamates As Anti-arthritis and Anti-osteoporosis Agentsmentioning

confidence: 99%

Section: B Sulfamates As Anti-arthritis and Anti-osteoporosis Agentsmentioning

confidence: 99%

Section: B Sulfamates As Anti-arthritis and Anti-osteoporosis Agentsmentioning

confidence: 99%

See 2 more Smart Citations

Sulfamates and their therapeutic potential

Winum¹,

Scozzafava²,

Montéro³

et al. 2004

Medicinal Research Reviews

196

153

View full text Add to dashboard Cite

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“…According to Walsh et al (1990), 25) evidence has accumulated which implicates uninhibited or increased leukotriene production in addition to prostaglandin inhibition as a more complete explanation for the NSAID-induced side effects. Thus, as more lipoxygenase (5-LO) inhibitory activity is introduced into NSAID pharmacophore, a commensurate decrease in ulceration is realized.…”

Section: Discussionmentioning

confidence: 99%

Antiedematogenic Activity of Two Thiazolidine Derivatives: N-Tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) Rhodanine (GS26) and N-Tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28)

Silva

Góes

Lima

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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The main limitation in the use of anti-inflammatory drugs or drugs that inhibit some aspects of inflammation is their secondary effects, especially on the gastro-intestinal tract, during chronic use. Therefore, anti-inflammatory drugs without such effects have been one of the main objectives of researchers. 1)Modern organic chemistry development has provided an increased number of substances for various therapeutic aims. Among the methods for obtaining new drugs, molecular modification or variation using the Bioisostery concept is often used. Using this chemical concept, substitute groups can be introduced in one or more positions of a main molecule, creating similar compounds with varied biological activities that can show interesting medical properties. With this process, we can analyze the influence of the modification of an atom or a group of atoms on the main molecule's biological activity. The molecular alterations can result in molecules with similar, antagonistic or more larger potent activity than that of the original compound.2)The thiazolidinic and imidazolidinic nuclei represent a category of compounds that present promising biological activities: insecticidal, 3) antimicrobial, antifungal, narcotic, sedative, anesthetic, anticonvulsive and nematocidal. 4) Góes et al. (1991) 5) showed that thiazolidine and imidazolidine derivatives (or isosters) possess antifungal (against Candida albicans and Neurospora crassa) and moderate antibiotic activity (against E. coli, S. aureus and others).Among the compounds that possess a thiazolidinic nucleus, 2,4-thiazolidinedione ( Fig. 1) and rhodanine (Fig. 2) were studied by Lima (1999) 6) with respect to the antiedematogenic properties of their isosters. In this study antiedematogenic activity was found for two bioisosters, N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28) (MWϭ476) (Fig. 3) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26) (MWϭ492) (Fig. 4). Studies related to acute toxicity (LD 50 ) of GS26 and GS28 in a range of oral doses of 25, 50, 100, 250, 500 and 1000 mg/kg did not indicate any toxicity. The aim of this study was to determine the existence of antiedematogenic properties on thiazolidinic isosters GS26 and GS28 in the response evoked by well-known edematogenic agents. Chemistry Two new compounds N-tryptophyl-5-(3,5-di-

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