Development of a Gram-Scale Synthesis of PBRM, an Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1

2019 ◽  
Vol 23 (11) ◽  
pp. 2323-2335 ◽  
Author(s):  
René Maltais ◽  
Donald Poirier
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Irreversible Inhibitor

Discovery of a Non-Estrogenic Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1 from 3-Substituted-16β-(m-carbamoylbenzyl)-estradiol Derivatives

2013 ◽  
Vol 57 (1) ◽  
pp. 204-222 ◽  
Author(s):  
René Maltais ◽  
Diana Ayan ◽  
Alexandre Trottier ◽  
Xavier Barbeau ◽  
Patrick Lagüe ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Irreversible Inhibitor ◽  
Estradiol Derivatives

The role of hepatic 11[b]-hydroxysteroid dehydrogenase type 1 in cholesterol homeostasis

2013 ◽  
pp. 1-1
Author(s):  
Kajal Manwani ◽  
Tak Y Man ◽  
Christopher J Kenyon ◽  
Ruth Andrew ◽  
Karen E Chapman ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Cholesterol Homeostasis

Macrophage-specific 11b-hydroxysteroid dehydrogenase type 1 deficiency promotes angiogenesis but impairs resolution of K/BxN serum induced arthritis

2013 ◽  
pp. 1-1
Author(s):  
Zhenguang Zhang ◽  
Agnes Coutinho ◽  
Patrick Hadoke ◽  
Donald Salter ◽  
Jonathan Seckl ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase

Suppression of 11[beta]-hydroxysteroid dehydrogenase type 1 target gene regulation by hypoxia

2016 ◽  
Author(s):  
Bushra Shammout ◽  
Adewonuola Alase ◽  
Miriam Wittmann ◽  
Paul Stewart ◽  
Ana Tiganescu
Keyword(s):  
Gene Regulation ◽  
Target Gene ◽  
Hydroxysteroid Dehydrogenase

scholarly journals 11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Keira Markey ◽  
James Mitchell ◽  
Hannah Botfield ◽  
Ryan S Ottridge ◽  
Tim Matthews ◽  
...  
Keyword(s):  
Intracranial Hypertension ◽  
Lumbar Puncture ◽  
Idiopathic Intracranial Hypertension ◽  
Controlled Trial ◽  
Hydroxysteroid Dehydrogenase ◽  
Opening Pressure ◽  
Double Blind ◽  
Randomized Controlled

Abstract Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18–55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m2] were randomized to AZD4017 (n = 17) or placebo (n = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: −2.8, 95% confidence interval: −7.1 to 1.5; P = 0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: −4.3 cmH2O (SD = 5.7); P = 0.009] but not in the placebo group [mean change: −0.3 cmH2O (SD = 5.9); P = 0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure (P = 0.005, R = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

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