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Benzoxazinone derivatives for treatment of skin diseases

A technology for benzoxazine and skin diseases, which is applied in the field of inhibiting the activity of skin proteases, and can solve the problem of not reporting compound selectivity data

Active Publication Date: 2016-11-16
SIXERA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] WO 2004 / 108139 describes some substituted benzoxazinone and thienoxazinone compounds as inhibitors of KLK7, but does not report any selectivity data for the described compounds

Method used

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  • Benzoxazinone derivatives for treatment of skin diseases
  • Benzoxazinone derivatives for treatment of skin diseases
  • Benzoxazinone derivatives for treatment of skin diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Selectivity of substituted 3,1-benzoxazin-4-ones as inhibitors of human proteases

[0051] Determination of the ICs of some substituted 3,1-benzoxazin-4-ones against a panel of human proteases 50 value.

[0052] KLK7 test

[0053] Material: recombinant human KLK7, substrate S-2586 (chromogenic substrate, cat.no.820894)

[0054] KLK7 activity was measured under the following conditions: 37°C, in 10mM sodium phosphate pH 7.2, 0.5M NaCl, KLK7 final concentration 2.5μg / mL (100nM), 1.0mM substrate, 5% DMSO inhibitor concentrations were 0μM, respectively. 0.1 μM, 0.5 μM, 1.0 μM and 5.0 μM, using a 96-well plate to measure the absorbance at 405 nm with a microplate reader (Spectramax).

[0055] KLK5 test

[0056] Material: recombinant human KLK5, substrate S-2288 (chromogenic substrate, cat.no.820852)

[0057] KLK5 activity was determined under the following conditions: 37°C, inhibition in 0.1mM Tris (trishydroxymethylaminomethane), pH 8.0, 0.15M NaCl, KLK5 final concentr...

Embodiment 2

[0081] Synthesis of 6-ethoxy-7-methoxy-2-(2-methylmercaptophenyl)-3,1-benzoxazin-4-one

[0082]

Embodiment 3

[0084] Synthesis of 2-(2-chlorophenyl)-6-ethoxy-7-methoxy-3,l-benzoxazin-4-one

[0085] Same as Example 2 but using in the third step

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Abstract

The present invention relates to methods and compositions for inhibiting the activity of skin proteases, especially human kallikrein 7 (KLK7), human kallikrein 5 (KLK5), and human kallikrein 14 (KLK14). More specifically, the invention relates to the use of substituted 3,1 -benzoxazin-4-ones being selective inhibitors of human skin kallikreins for the treatment of skin diseases, more specifically for the treatment of inflammatory skins diseases, especially Netherton syndrome.

Description

technical field [0001] The present invention relates to methods and compositions for inhibiting the activity of skin proteases, in particular human kallikrein 7 (KLK7), human kallikrein 5 (KLK5) and human kallikrein 14 (KLK14 ). More specifically, the present invention relates to the use of substituted 3,1-benzoxazin-4-ones as selective inhibitors of human skin kallikrein for the treatment of skin diseases, more specifically for Treatment of inflammatory skin disorders, especially Netherton syndrome. Background technique [0002] KLK7 (hK7, or cornified chymotrypsin (SCCE), Swissprot P49862) is an S1 serine protease of the kallikrein gene family that exhibits chymotrypsin-like activity. KLK7 is mainly expressed in the skin and appears to play an important role in skin physiology (Egelrud. 1993. Purification and preliminary characterization of stratum corneum chymotryptic enzyme: a proteinase that may be involved indesquamation. J. Invest. Dermatol. 101, 200-204; Skytt et ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/20A61K31/536A61P17/04A61P17/06
CPCA61K31/536C07D265/22C07D498/04A61K31/539A61P17/00A61P17/02A61P17/04A61P17/06A61P29/00A61P37/08
Inventor F·沃格贝里G·莱昂纳德松
Owner SIXERA PHARMA
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