Citation

Tan X, Soualmia F, Furio L, Renard JF, Kempen I, Qin L, Pagano M, Pirotte B, El Amri C, Hovnanian A, Reboud-Ravaux M. J. Med. Chem. 2015; 58(2): 598-612.

Copyright

(Copyright © 2015, American Chemical Society)

DOI

10.1021/jm500988d

PMID

unavailable

Abstract

The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates the kallikrein proteolytic cascade) constitutes an innovative way to treat some skin diseases such as Netherton syndrome. We present here the inhibitory properties of coumarin-3-carboxylate derivatives against these enzymes. Our small collection of these versatile organic compounds was enriched by newly synthesized derivatives in order to obtain molecules selective against one, two, three enzymes or acting on the four ones. We evidenced a series of compounds with IC50 values in the nanomolar range. A suicide mechanism was observed against kallikrein 7 whereas the inactivation was either definitive (suicide type) or transient for kallikreins 5 and 14, and matriptase. Most of these potent inhibitors were devoid of cytotoxicity toward healthy human keratinocytes. In situ zymography investigations on skin sections from human kallikrein 5 transgenic mouse revealed significant reduction of the global proteolytic activity by several compounds. © 2014 American Chemical Society.

Language: en

Keywords

Humans; human; controlled study; human cell; unclassified drug; drug mechanism; nonhuman; pH; physiology; mouse; drug screening; animal experiment; enzyme inhibition; animal model; drug synthesis; serine proteinase inhibitor; suicide substrate; protein degradation; keratinocyte; Article; skin disease; Skin Diseases; carboxylic acid derivative; molecular model; Serine Endopeptidases; structure activity relation; Structure-Activity Relationship; antagonists and inhibitors; serine proteinase; enzymology; coumarin derivative; Coumarins; (3 halo)phenyl 6 (hydroxymethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 1 naphthyl 2 oxo 2h 1 benzopyran 3 carboxylate; 2 carboxyphenyl 6 (chloromethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 2 methoxycarbonylphenyl 6 (chloromethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 2 naphthyl 2 oxo 2h 1 benzopyran 3 carboxylate; 3 bromophenyl 6 (bromomethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 3 carbamoylphenyl 6 (chloromethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 3 carboxyphenyl 6 (chloromethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 3 chlorophenyl 6 (bromomethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 3 chlorophenyl 6 (fluoromethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 3 chlorophenyl 6 (hydroxymethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 3 fluorophenyl 6 (bromomethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 3 fluorophenyl 6 (hydroxymethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 3 methoxycarbonylphenyl 6 (chloromethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; 4 methoxycarbonylphenyl 6 (chloromethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; di 3 bromophenyl malonate; isoquinol 1 yl 2 oxo 2h 1 benzopyran 3 carboxylate; kallikrein; kallikrein 14; kallikrein 5; kallikrein inhibitor; Kallikreins; KLK5 protein, human; KLK7 protein, human; matriptase; phenyl 6 (bromomethyl) 2 oxo 2h1 benzopyran 3 carboxylate; phenyl 6 (hydroxymethyl) 2 oxo 2h 1 benzopyran 3 carboxylate; Serine Proteinase Inhibitors; stratum corneum chymotryptic enzyme; zymography