Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors. Issue 20 (15th October 2019)

• Record Type: Journal Article
• Authors: Walker, Ann L.; Denis, Alexis; Bingham, Ryan P.; Boulliot, Anne; Edgar, Emma V.; Ferrie, Alan; Holmes, Duncan S.; Laroze, Alain; Liddle, John; Fouchet, Marie-Helene; Moquette, Alexandre; Nassau, Pam; Pearce, Andrew C.; Polyakova, Oxana; Smith, Kathrine J.; Thomas, Pamela; Thorpe, James H.; Trottet, Lionel; Wang, Yichen; Hovnanian, Alain
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 20(2019)
• Publication Date: 2019-10-15
• Subjects: KLK1 kallikrein 1 -- KLKB1 kallikrein B1 -- KLK5 kallikrein 5 -- KLK7 kallikrein 7 -- KLK8 kallikrein 8 -- KLK14 kallikrein 14 -- LCMS liquid chromatography-mass spectrometry -- LEKTI lympho-epithelial kazal-type-related inhibitor -- NS Netherton Syndrome -- NMR nuclear magnetic resonance -- 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.2019.126675
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.