Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of highly potent inhibitors enabling a proof of principle study in rodents

Estradiol is the most potent estrogen in humans. It is known to be involved in development and proliferation of estrogen dependent diseases such as breast cancer and endometriosis. The last step of its biosynthesis is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β- HSD1) which consequently is a promising target for the treatment of these diseases. Recently, we reported on bicyclic substituted hydroxyphenylmethanones (BSHs) as potent inhibitors of 17β-HSD1. Our goal in this study was to obtain a suitable candidate for proof of principle (PoP) study in an animal disease model for endometriosis. At a first stage, we focused on rational structural modifications in this compound class with the aim of gaining more insight into its structure-activity relationship (SAR). At a second stage, supplementary substituents were added to the most active core to enhance activity towards both human and rodent 17β-HSD1 enzymes. Thus, the most potent nonsteroidal inhibitors of h17β-HSD1 described so far have been discovered. Furthermore, a successful strategy was applied to improve the metabolic stability in human liver microsomes (S9 fraction). Compound II.43, one of the most interesting h17β-HSD1 inhibitors in this study, showed a very good metabolic stability towards both phase I and II in human liver microsomes (S9 fraction), with 72 % remaining after 60 min. In addition, inhibition of rodent 17β-HSD1 was significantly improved. Compound II.47 could be considered a possible candidate for a PoP study (63 % inhibition of rat 17β-HSD1 @ 250 nM).Estradiol ist das potenteste Estrogen beim Menschen. Es ist bekanntermaßen an Entstehung und Fortschreiten Estrogen-abhängiger Erkrankungen wie Brustkrebs und Endometriose beteiligt. Der letzte Schritt seiner Biosynthese wird durch 17β-Hydroxysteroid Dehydrogenase Typ 1 (17β-HSD1) katalysiert. Daher ist dieses Enzym ein vielversprechendes Target für die Behandlung dieser Erkrankungen. Kürzlich berichteten wir über bicyclisch substituierte Hydroxyphenylmethanone (BSHs), die potente Inhibitoren der 17β-HSD1 darstellen. Das Ziel der vorliegenden Studie bestand darin, einen Wirkstoff-Kandidaten zu erhalten, der für die Indikation Endometriose eine proof of principle- (PoP-)Studie in einem Krankheitsmodell am Tier (Nager) ermöglicht. Dazu wurden zunächst rationale Strukturmodifikationen durchgeführt, die das Ziel hatten, die Struktur-Wirkbeziehungen (SAR) dieser Wirkstoffklasse zu beleuchten. Aus den resultierenden Verbindungen wurde anschließend diejenige mit den interessantesten biologischen Eigenschaften ausgewählt, um durch Einfügen weiterer Substituenten die Hemmaktivität sowohl gegenüber der humanen als auch gegenüber Nager-17β-HSD1 weiter zu steigern. Aus diesen Arbeiten gingen die potentesten nichtsteroidalen Inhibitoren der humanen 17β-HSD1 hervor, die bisher beschrieben wurden. Darüber hinaus wurde erfolgreich eine Strategie zur Verbesserung der metabolischen Stabilität in humanen Lebermikrosomen (S9-Fraktion) angewandt. Verbindung II.43, eine der interessantesten Verbindungen der Studie, zeigt eine sehr hohe metabolische Stabilität: Nach 60 minütiger Inkubation liegen 72 % der Verbindung unverändert vor. Auch die Hemmung des Nager-Enzyms konnte signifikant verbessert werden. Verbindung II.47 kann als möglicher Kandidat für eine PoP-Studie an der Ratte angesehen werden (63 % Hemmung der Ratten-17β-HSD1 bei 250 nM)

Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of highly potent inhibitors enabling a proof of principle study in rodents

Estradiol is the most potent estrogen in humans. It is known to be involved in development and proliferation of estrogen dependent diseases such as breast cancer and endometriosis. The last step of its biosynthesis is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β- HSD1) which consequently is a promising target for the treatment of these diseases. Recently, we reported on bicyclic substituted hydroxyphenylmethanones (BSHs) as potent inhibitors of 17β-HSD1. Our goal in this study was to obtain a suitable candidate for proof of principle (PoP) study in an animal disease model for endometriosis. At a first stage, we focused on rational structural modifications in this compound class with the aim of gaining more insight into its structure-activity relationship (SAR). At a second stage, supplementary substituents were added to the most active core to enhance activity towards both human and rodent 17β-HSD1 enzymes. Thus, the most potent nonsteroidal inhibitors of h17β-HSD1 described so far have been discovered. Furthermore, a successful strategy was applied to improve the metabolic stability in human liver microsomes (S9 fraction). Compound II.43, one of the most interesting h17β-HSD1 inhibitors in this study, showed a very good metabolic stability towards both phase I and II in human liver microsomes (S9 fraction), with 72 % remaining after 60 min. In addition, inhibition of rodent 17β-HSD1 was significantly improved. Compound II.47 could be considered a possible candidate for a PoP study (63 % inhibition of rat 17β-HSD1 @ 250 nM).Estradiol ist das potenteste Estrogen beim Menschen. Es ist bekanntermaßen an Entstehung und Fortschreiten Estrogen-abhängiger Erkrankungen wie Brustkrebs und Endometriose beteiligt. Der letzte Schritt seiner Biosynthese wird durch 17β-Hydroxysteroid Dehydrogenase Typ 1 (17β-HSD1) katalysiert. Daher ist dieses Enzym ein vielversprechendes Target für die Behandlung dieser Erkrankungen. Kürzlich berichteten wir über bicyclisch substituierte Hydroxyphenylmethanone (BSHs), die potente Inhibitoren der 17β-HSD1 darstellen. Das Ziel der vorliegenden Studie bestand darin, einen Wirkstoff-Kandidaten zu erhalten, der für die Indikation Endometriose eine proof of principle- (PoP-)Studie in einem Krankheitsmodell am Tier (Nager) ermöglicht. Dazu wurden zunächst rationale Strukturmodifikationen durchgeführt, die das Ziel hatten, die Struktur-Wirkbeziehungen (SAR) dieser Wirkstoffklasse zu beleuchten. Aus den resultierenden Verbindungen wurde anschließend diejenige mit den interessantesten biologischen Eigenschaften ausgewählt, um durch Einfügen weiterer Substituenten die Hemmaktivität sowohl gegenüber der humanen als auch gegenüber Nager-17β-HSD1 weiter zu steigern. Aus diesen Arbeiten gingen die potentesten nichtsteroidalen Inhibitoren der humanen 17β-HSD1 hervor, die bisher beschrieben wurden. Darüber hinaus wurde erfolgreich eine Strategie zur Verbesserung der metabolischen Stabilität in humanen Lebermikrosomen (S9-Fraktion) angewandt. Verbindung II.43, eine der interessantesten Verbindungen der Studie, zeigt eine sehr hohe metabolische Stabilität: Nach 60 minütiger Inkubation liegen 72 % der Verbindung unverändert vor. Auch die Hemmung des Nager-Enzyms konnte signifikant verbessert werden. Verbindung II.47 kann als möglicher Kandidat für eine PoP-Studie an der Ratte angesehen werden (63 % Hemmung der Ratten-17β-HSD1 bei 250 nM)

Pediatric Dermatology In Family Medicine: Common Conditions And Management Strategies

Among the most prevalent disorders are those related to the skin.  However, in medical education and training, this class of illnesses is frequently disregarded. The first line of defence for the treatment of common dermatological diseases is a family physician. The purpose of our study was to evaluate the particular identification, management, encountering, and referral practices related to dermatological illnesses in family care. We also looked into the challenges and opportunities that family doctors experience in family medicine and saw a few of the paediatric dermatological diseases that family doctors may encounter.  Finding areas of weakness in the clinical therapy of certain dermatological disorders, however, will be aided by assessing how family doctors treat particular ailments. Thus, this needs assessment might serve as a foundation for future research on the efficacy of family medicine in treating common paediatric dermatological problems as well as aid in the development of evidence-based training for family physicians in the area

Overview on Juvenile Primary Fibromyalgia Syndrome

JPFS (juvenile primary fibromyalgia syndrome) is a musculoskeletal pain illness that affects children and adolescents. The intricacy of the clinical picture in JPFS has not been adequately characterized in the literature. JFMS symptoms are sometimes difficult to compare to adult fibromyalgia syndrome since many of them are "medically unexplained" and frequently overlap with other medical disorders.  The etiology of the illness is multifaceted, with impaired central pain processing being a significant contributor. Musculoskeletal pain that is severe and pervasive is the defining symptom. Other signs and symptoms include headaches, stiffness, subjective joint swelling, sleep and mood disorders, and headaches. Multiple sensitive spots might be found during a physical examination. The diagnosis has certain criteria and is clinical. Early detection and treatment are crucial. The gold standard of care combines a variety of modalities, but most significantly, exercise and cognitive behavioral therapy. The outlook varies, and symptoms might last well into adulthood. Discussing the epidemiology, etiology, pathophysiology, clinical symptoms, diagnosis, and management of JPFS is the goal of the review

A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms

Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter-gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI-tobramycin (Tob) combination against PA biofilms using a tailor-made squalene-derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32-fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker-mediated therapy against PA infections opening up avenues for preclinical development

A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms

Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry‐driven hit‐to‐lead optimization and in‐depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter‐gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI‐tobramycin (Tob) combination against PA biofilms using a tailor‐made squalene‐derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32‐fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker‐mediated therapy against PA infections opening up avenues for preclinical development.H2020 Marie Skłodowska-Curie Action