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Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome

[Display omitted] 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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-06, Vol.29 (12), p.1454-1458
Main 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
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Language:English
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2019.04.022