Hydroxysteroid-dehydrogenase Inhibitors

Rationale for the Use of 17 -Hydroxysteroid-dehydrogenase Inhibitors in Cancer Treatment 

Several potent anti-estrogens also have a potential to be used as 17/f-HSD inhibitors because some of them have a dual site of inhibitory action they block both the estrogen receptor (anti-estrogen effect) and estrogen formation (inhibitory effect on 17/f-HSD). Despite the complexity of a dually active agent, such inhibitors have interesting properties suitable for their potential use in the treatment of estrogen-sensitive diseases, but their potency and selectivity for 17/1-HSDl have to be improved [98]. 

Historically, the 17)6-HSDs have been classified as reversible enzymes, i.e. being able to catalyse both reductive and oxidative conversions. However, Luu-The and colleagues [95,100] observed that, although the activity of 17/1- 

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Trilostane is 13-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones and is comparable to aminoglutethimide. Trilostane s adverse effects are predominantly gastrointestinal adverse effects occur in about 50% of patients with both trilostane and aminoglutethimide. There is no cross-resistance or crossover of side effects between these compounds. Trilostane is not available in the USA. 

Andrews, R C., Rooyackers, O., Walker, B. R (2003) Effects of the llfi-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 88, 285-291. 

R. Xu, B.-C. Sang, M. Navre, and D. B. Kassel, Cell-Based Assay Screening lip-Hydroxysteroid Dehydrogenase Inhibitors Using Liquid Chromatography/ Tandem Mass Spectrometry Detection, Rapid Commun. Mass. Spectrom. 20 (2006), 1-5. 

FIGURE 11.54 Libraries of type 3 17 3-hydroxysteroid dehydrogenase inhibitors. (From Maltais, R., Luu-The, V., and Poirier, D., Parallel solid-phase synthesis of 3 3-peptido-3 -hydroxy-5 -androstan-17-one derivatives for inhibition of type 3 17P-hydroxysteroid dehydrogenase, Bioorg. Med. Chem., 9, 3101, 2001 Maltais, R., Luu-The, V., and Poirier, D., Synthesis and optimization of a new family of type 17P-hydroxysteroid dehydrogenase inhibitors by parallel liquid phase chemistry, J. Med. Chem., 45, 640, 2002.)... 

Maltais, R., Luu-The, V., and Poirier, D., Synthesis and optimization of a new family of type 17 3-hydroxysteroid dehydrogenase inhibitors by parallel liquid phase chemistry, J. Med. Chem., 45, 640, 2002. 

The enzyme 3a-hydroxysteroid dehydrogenase plays a key role in this transport across the hepatocyte. A particularly elegant experiment demonstrated the role of the 3a-hydroxysteroid dehydrogenase, by using [ H] at the 3p hydrogen to show cyclical oxidation-reduction of the 3a-hydroxyl with no accumulation of 3-keto bile acids. Confirmation was obtained by use of indo-methacin, an inhibitor of 3a-hydroxysteroid dehydrogenase, which decreased... 

Similar to the challenges outlined in Chapter 2, the fact that most Chinese herbal medicines are complex mixtures of multiple active constituents further complicates the interpretation of study data, as well as extrapolation to other botanical products. Japanese Kampo (traditional Chinese herbal mixtures) prescriptions have been used for many years to treat different chronic conditions and are presently manufactured in Japan as drugs with standardized quantities and qualities of constituents. Homma et al. (51) evaluated the effect of three commonly used Japanese Kampo prescriptions, Sho-saiko-to (Xiao Chai Hu Tang), Saiboku-to, and Sairei-to, on prednisolone pharmacokinetics in humans. All three botanical prescriptions contain glycyrrhizin, a strong inhibitor of 11-p-hydroxysteroid dehydrogenase. Chen et al. (52) had shown that glycyrrhizin decreased plasma clearance and increased AUC and concentration of prednisolone. 

Barf, T., Williams, M. (2006) Recent progress in llb-hydroxysteroid dehydrogenase type 1 (llb-HSDl) inhibitor development. Drugs Future 31(3), 231-243. 

U. (2006) Active site variability of type 1 llb-hydroxysteroid dehydrogenase revealed by selective inhibitors and cross-species comparisons. Mol Cell Endocrinol 248, 26-33. 

Olson, S., Balkovec, J., Gao, Y. -D, et al. (2004) Selective inhibitors of llfi-hydroxysteroid dehydrogenase type 1. Adamantyl triazoles as pharmacological agents for the treatment of metabolic syndrome. Keystone Symp Abst X2-239. 

In the fields of allergy and respiration, examples include 2-oxo-3-aminoazepine derivatives which act as dual neurokinin (tachykinin) NK1/NK2 receptor probes for development of options for treatment of asthsma and other airway diseases <07BMCL890> and benzo[l, 5]diazepine derivatives as new non-steroidal inhibitors of 17-P-hydroxysteroid dehydrogenase, an enzyme associated with hormone-dependent and neuronal diseases <07JEIMC29>. 

Schuster et al developed ligand-based pharmacophore models for 11 (3-hydroxysteroid dehydrogenase (11(3-HSD) inhibitors.By VS they were able to identify inhibitors of this enzyme active in the nanomolar range. 

Diederich S, Grossmann C, Hanke B, et al. In the search for specific inhibitors of human 11 (3-hydroxysteroid-dehydrogenases (11(3-HSDs) ohenodeoxyoholio aoid selectively inhibits 11(3-HSD-I. Eur J Endocrinol 2000 142 200-207. 

Barf T, Vallgarda J, Emond R, et al. Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and seleotive inhibitors of the 11 (3-hydroxysteroid dehydrogenase type 1. J Med Chem 2002 45 3813-3815. 

Schuster, D., Nashev, L.G., Kirchmair, J., Laggner, C., Wolber, G., Langer, T., and Odermatt, A. (2008) Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries. Journal of Medicinal Chemistry, 51, 4188 199. 

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