Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors

Gargano, Emanuele M.; Perspicace, Enrico; Hanke, Nina; Carotti, Angelo; Marchais‐Oberwinkler, Sandrine; Hartmann, Rolf W.

doi:10.1016/j.ejmech.2014.09.061

Cited by 17 publications

(21 citation statements)

References 57 publications

(40 reference statements)

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“…Very sharp SAR could be observed in this class of compounds. In general, the 2,5-disubstituted thiophene derivatives were less active towards the murine enzyme than towards the human ortholog, except for compound 85 ( figure 18), which in protein preparations was four times more potent against murine 17β-HSD2 (IC 50 = 54 nM) than against the human enzyme (IC50 = 235 nM) with a strong selectivity over h17β-HSD1 (SF1/2 = 95) and low affinities to ERα and β (Perspicace et al 2014).…”

Section: Figure 18mentioning

confidence: 99%

“…Compound 86 ( figure 19) showed a half-life greater than 120 minutes in human liver microsomes (S9 fraction), moderate activity towards 17β-HSD2 and selectivity over 17β-HSD1 (SF1/2 = 10). In addition, the compound displayed no affinity for the estrogen receptors (Gargano et al 2014). Gargano et al aimed at identifying a compound which can be used for a proof of concept study in a mouse model for osteoporosis beside being a suitable potential therapeutic for treating osteoporosis in humans.…”

Section: Figure 19mentioning

confidence: 99%

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Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah

Abdelsamie²,

Frotscher

2019

Molecular and Cellular Endocrinology

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During the past 25 years, the modulation of estrogen action by inhibition of 17β-hydroxysteroid dehydrogenase types 1 and 2 (17β-HSD1 and 17β-HSD2), respectively, has been pursued intensively. In the search for novel treatment options for estrogen-dependent diseases (EDD) and in order to explore estrogenic signaling pathways, a large number of steroidal and nonsteroidal inhibitors of these enzymes has been described in the literature. The present review gives a survey on the development of inhibitor classes as well as the structural formulas and properties of their most interesting representatives. In addition, rationally designed dual inhibitors of both 17β-HSD1 and steroid sulfatase (STS) as well as the first inhibitors of 17β-HSD14 are covered.

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Section: Figure 18mentioning

confidence: 99%

Section: Figure 19mentioning

confidence: 99%

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah

Abdelsamie²,

Frotscher

2019

Molecular and Cellular Endocrinology

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“…On the other hand, the protein precipitation method is a very simple method and is required for terminating the enzymatic reaction, so it was carried out for the preparation of rat liver S9 fraction samples. Acetonitrile was chosen as the solvent for protein precipitation as it provided clean samples, good recovery, and a high response …”

Section: Resultsmentioning

confidence: 99%

“…Acetonitrile was chosen as the solvent for protein precipitation as it provided clean samples, good recovery, and a high response. 35…”

Section: Optimization Of Human Plasma and Rat Liver S9 Fraction Sammentioning

confidence: 99%

Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile

Moussa

El‐Zaher

El-Ashrey

et al. 2019

Drug Testing and Analysis

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With the aim of studying their in vitro and in vivo pharmacokinetics, new chromatographic methods were developed for the determination of three new roflumilast synthetic analogs (I−III) as PDE‐4B inhibitors in rat liver S9 fraction, phosphate buffered saline, pH 7.4, and human and rat plasma. The developed high performance liquid chromatography−ultra violet (HPLC−UV) methods were performed on a Zorbax Eclipse C8 column and UV detection was carried out at 215 nm. The three compounds were tested for their metabolic stability and were found to be metabolically more stable than roflumilast especially the 2‐mercaptobenzothiazol‐6‐yl analog (III) which displayed an in vitro half‐life time (247.55 minutes) higher than that of roflumilast (12.29 minutes) and a low in vitro clearance of 5.67 mL/min./kg. Possible phase I metabolites were investigated using ultra‐performance liquid chromatography−tandem mass spectrometry (UPLC–MS/MS) showing hydroxylation of the unsubstituted benzothiazol‐2‐yl (I) and benzothiazole‐6‐yl (II) analogs and a cleaved benzothiazole metabolite of the 2‐mercaptobenzothiazol‐6‐yl analog (III). Plasma protein binding affinity was tested using equilibrium membrane dialysis method showing a very high percentage (more than 95%) of plasma protein binding of compounds I and II where compound III exhibited lower percentage (53.71%) demonstrating its accessibility for tissue distribution. Also, a UPLC–MS/MS method was developed using an Acquity UPLC BEH shield RP C18 column to be applied to an in vivo pharmacokinetic study in rats following a subcutaneous dose (1 mg/kg). Compounds I−III showed improved in vivo pharmacokinetic parameters especially compound III which displayed a half‐life 3‐fold greater than roflumilast (21 hours) and a Cmax value of 113.958 ng/mL. Accordingly, this new chemical entity should be subjected to further investigation as it can be a good drug candidate for treating chronic obstructive pulmonary disease.

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“…In the 2,5-thiophene amide class (compounds 1a-2g ), h 17 β -HSD2 inhibitors [ 13 , 14 ], a broad range of inhibitory activities was detected, depending on the substitution pattern; the most active compounds show IC 50 values around 60 nM ( Table 1 ). Conversely, the inhibitory activity towards m 17 β -HSD2 was only marginally affected by these changes (inhibitory activity around 30% at 1 μM).…”

Section: Resultsmentioning

confidence: 99%

17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog

et al. 2015

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Design and synthesis of a new class of inhibitors for the treatment of osteoporosis and its comparative h17β-HSD2 and m17β-HSD2 SAR study are described. 17a is the first compound to show strong inhibition of both h17β-HSD2 and m17β-HSD2, intracellular activity, metabolic stability, selectivity toward h17β-HSD1, m17β-HSD1 and estrogen receptors α and β as well as appropriate physicochemical properties for oral bioavailability. These properties make it eligible for pre-clinical animal studies, prior to human studies.

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Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors

Cited by 17 publications

References 57 publications

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile

17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog

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