Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome. Issue 12 (15th June 2019)

• Record Type: Journal Article
• Authors: Walker, Ann L.; Bingham, Ryan P.; Edgar, Emma V.; Ferrie, Alan; Holmes, Duncan S.; Liddle, John; Polyakova, Oxana; Rella, Monika; Smith, Kathrine J.; Thorpe, James H.; Wang, Yichen; White, Gemma V.; Young, Robert J.; Hovnanian, Alain
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 12(2019)
• Page Start: 1454
• Page End: 1458
• Publication Date: 2019-06-15
• Subjects: KLK1 kallikrein 1 -- KLKB1 kallikrein B1 -- KLK5 kallikrein 5 -- KLK7 kallikrein 7 -- KLK8 kallikrein 8 -- LEKTI lympho-epithelial kazal-type-related inhibitor -- NS Netherton syndrome -- SPINK5 serine protease inhibitor kazal-type 5 gene; KLK1 -- KLK5 -- KLKB1 -- LEKTI -- Netherton syndrome -- SPINK5; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.04.022
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The connection between Netherton syndrome and overactivation of epidermal/dermal proteases particularly KLK5 has been well established. To treat sufferers of this severe condition we wished to develop a topical KLK5 inhibitor in order to normalise epidermal shedding and reduce the associated inflammation and itching. In this paper we describe structure-based optimisation of a series of brightly coloured weak KLK5 inhibitors into colourless, non-irritant molecules with good KLK5 activity and selectivity over a range of serine proteases.