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

Gargano EM, Allegretta G, Perspicace E, Carotti A, Van Koppen C, Frotscher M, Marchais-Oberwinkler S, Hartmann RW - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Synthesis of 1,4-Phenyl Retroamide Derivative 24a.Reagents and conditions: (i) Et3N, CH2Cl2, room temperature, overnight; (ii) DME/EtOH/H2O (1:1:1), Cs2CO3, Pd(PPh3)4, microwave irradiation (150°C, 150W, 20 min).
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pone.0134754.g004: Synthesis of 1,4-Phenyl Retroamide Derivative 24a.Reagents and conditions: (i) Et3N, CH2Cl2, room temperature, overnight; (ii) DME/EtOH/H2O (1:1:1), Cs2CO3, Pd(PPh3)4, microwave irradiation (150°C, 150W, 20 min).

Mentions: The synthesis of the retroamide 24a, displayed in Fig 4, follows a two-step procedure.


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

Gargano EM, Allegretta G, Perspicace E, Carotti A, Van Koppen C, Frotscher M, Marchais-Oberwinkler S, Hartmann RW - PLoS ONE (2015)

Synthesis of 1,4-Phenyl Retroamide Derivative 24a.Reagents and conditions: (i) Et3N, CH2Cl2, room temperature, overnight; (ii) DME/EtOH/H2O (1:1:1), Cs2CO3, Pd(PPh3)4, microwave irradiation (150°C, 150W, 20 min).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4521925&req=5

pone.0134754.g004: Synthesis of 1,4-Phenyl Retroamide Derivative 24a.Reagents and conditions: (i) Et3N, CH2Cl2, room temperature, overnight; (ii) DME/EtOH/H2O (1:1:1), Cs2CO3, Pd(PPh3)4, microwave irradiation (150°C, 150W, 20 min).
Mentions: The synthesis of the retroamide 24a, displayed in Fig 4, follows a two-step procedure.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus