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

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 towar...

Descripción completa

Detalles Bibliográficos
Autores principales: Gargano, Emanuele M., Allegretta, Giuseppe, Perspicace, Enrico, Carotti, Angelo, Van Koppen, Chris, Frotscher, Martin, Marchais-Oberwinkler, Sandrine, Hartmann, Rolf W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521925/
https://www.ncbi.nlm.nih.gov/pubmed/26230928
http://dx.doi.org/10.1371/journal.pone.0134754
_version_ 1782383885166837760
author Gargano, Emanuele M.
Allegretta, Giuseppe
Perspicace, Enrico
Carotti, Angelo
Van Koppen, Chris
Frotscher, Martin
Marchais-Oberwinkler, Sandrine
Hartmann, Rolf W.
author_facet Gargano, Emanuele M.
Allegretta, Giuseppe
Perspicace, Enrico
Carotti, Angelo
Van Koppen, Chris
Frotscher, Martin
Marchais-Oberwinkler, Sandrine
Hartmann, Rolf W.
author_sort Gargano, Emanuele M.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4521925
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-45219252015-08-06 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog Gargano, Emanuele M. Allegretta, Giuseppe Perspicace, Enrico Carotti, Angelo Van Koppen, Chris Frotscher, Martin Marchais-Oberwinkler, Sandrine Hartmann, Rolf W. PLoS One Research Article 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. Public Library of Science 2015-07-31 /pmc/articles/PMC4521925/ /pubmed/26230928 http://dx.doi.org/10.1371/journal.pone.0134754 Text en © 2015 Gargano et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Gargano, Emanuele M.
Allegretta, Giuseppe
Perspicace, Enrico
Carotti, Angelo
Van Koppen, Chris
Frotscher, Martin
Marchais-Oberwinkler, Sandrine
Hartmann, Rolf W.
17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog
title 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog
title_full 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog
title_fullStr 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog
title_full_unstemmed 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog
title_short 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog
title_sort 17β-hydroxysteroid dehydrogenase type 2 inhibition: discovery of selective and metabolically stable compounds inhibiting both the human enzyme and its murine ortholog
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521925/
https://www.ncbi.nlm.nih.gov/pubmed/26230928
http://dx.doi.org/10.1371/journal.pone.0134754
work_keys_str_mv AT garganoemanuelem 17bhydroxysteroiddehydrogenasetype2inhibitiondiscoveryofselectiveandmetabolicallystablecompoundsinhibitingboththehumanenzymeanditsmurineortholog
AT allegrettagiuseppe 17bhydroxysteroiddehydrogenasetype2inhibitiondiscoveryofselectiveandmetabolicallystablecompoundsinhibitingboththehumanenzymeanditsmurineortholog
AT perspicaceenrico 17bhydroxysteroiddehydrogenasetype2inhibitiondiscoveryofselectiveandmetabolicallystablecompoundsinhibitingboththehumanenzymeanditsmurineortholog
AT carottiangelo 17bhydroxysteroiddehydrogenasetype2inhibitiondiscoveryofselectiveandmetabolicallystablecompoundsinhibitingboththehumanenzymeanditsmurineortholog
AT vankoppenchris 17bhydroxysteroiddehydrogenasetype2inhibitiondiscoveryofselectiveandmetabolicallystablecompoundsinhibitingboththehumanenzymeanditsmurineortholog
AT frotschermartin 17bhydroxysteroiddehydrogenasetype2inhibitiondiscoveryofselectiveandmetabolicallystablecompoundsinhibitingboththehumanenzymeanditsmurineortholog
AT marchaisoberwinklersandrine 17bhydroxysteroiddehydrogenasetype2inhibitiondiscoveryofselectiveandmetabolicallystablecompoundsinhibitingboththehumanenzymeanditsmurineortholog
AT hartmannrolfw 17bhydroxysteroiddehydrogenasetype2inhibitiondiscoveryofselectiveandmetabolicallystablecompoundsinhibitingboththehumanenzymeanditsmurineortholog

Ejemplares similares