title: Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™).
abstract: Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment in early Alzheimer's disease (AD). We sought to discover novel, brain-penetrant 11β-HSD1 inhibitors as potential medicines for the treatment of AD.
  
  
  
  Medicinal chemistry optimization of a series of amido-thiophene analogues was performed to identify potent and selective 11β-HSD1 inhibitors with optimized oral pharmacokinetics able to access the brain. Single and multiple ascending dose studies were conducted in healthy human subjects to determine the safety, pharmacokinetic and pharmacodynamic characteristics of the candidate compound.
  
  
  
  UE2343 was identified as a potent, orally bioavailable, brain-penetrant 11β-HSD1 inhibitor and selected for clinical studies. No major safety issues occurred in human subjects. Plasma adrenocorticotropic hormone was elevated (a marker of systemic enzyme inhibition) at doses of 10 mg and above, but plasma cortisol levels were unchanged. Following multiple doses of UE2343, plasma levels were approximately dose proportional and the terminal t1/2ranged from 10 to 14 h. The urinary tetrahydrocortisols/tetrahydrocortisone ratio was reduced at doses of 10 mg and above, indicating maximal 11β-HSD1 inhibition in the liver. Concentrations of UE2343 in the CSF were 33% of free plasma levels, and the peak concentration in CSF was ninefold greater than the UE2343 IC50.
  
  
  
  UE2343 is safe, well tolerated and reaches the brain at concentrations predicted to inhibit 11β-HSD1. UE2343 is therefore a suitable candidate to test the hypothesis that 11β-HSD1 inhibition in brain improves memory in patients with AD.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McBride
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Binnie
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Sooy
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
authors.affiliation: Charles River Laboratories, Harlow, UK.
authors.forename: T David
authors.initials: TD
authors.lastname: Pallin
authors.affiliation: Corcept Therapeutics, Menlo Park, California, USA.
authors.forename: Hazel J
authors.initials: HJ
authors.lastname: Hunt
authors.affiliation: Domainex Limited, Cambridge, UK.
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Perrior
authors.affiliation: Actinogen Medical Ltd, Sydney, New South Wales, Australia.
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Ruffles
authors.affiliation: Actinogen Medical Ltd, Sydney, New South Wales, Australia.
authors.forename: J William
authors.initials: JW
authors.lastname: Ketelbey
authors.affiliation: Alan Boyd Consultants Ltd, Crewe, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Boyd
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D013760:Tetrahydrocortisol / Q000652:urine; D013761:Tetrahydrocortisone / Q000652:urine; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014326:Tropanes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D013876:Thiophenes; D014326:Tropanes; C000621522:UE2343; D013761:Tetrahydrocortisone; D013760:Tetrahydrocortisol; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone