Cyclic urea compounds as granzyme b inhibitors

a technology of granzyme b and compound, applied in the field of granzyme b inhibitors, can solve the problems of limited use of biological inhibitors such as serpins, insufficient potency or specificity to be effective treatments for granzyme-b-related diseases, disorders, and conditions, and achieve the effects of reducing the appearance of ageing in the skin, reducing the number of side effects, and/or inhibiting the appearance of ageing

Active Publication Date: 2019-05-23
VIDA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0051]Cosmetic compositions comprising a Granzyme B inhibitor compound of the invention and a cosmetically acceptable carrier are also provided, as are methods for using the compositions to treat, reduce, and / or inhibit the appearance of ageing in the skin.

Problems solved by technology

Nonspecific inhibitors (such as isocoumarins) are not sufficiently potent or specific to be effective treatments for Granzyme-B-related diseases, disorders, and conditions.
Likewise, the use of biological inhibitors such as serpins is limited by the ability to deliver the inhibitor to the target mammal, the cost of manufacturing the biological agents, and other, off-target activities, such as inhibition of other serine proteases such as human neutrophil elastase (Dahlen et al., (1999), Biochim. Biophys. Acta, 1451(2-3), 233-41), Caspase-1 (Annaud et al., (1999), Biochem. J., September 15; 342 Pt3, 655-65; Krieg et al., (2001), Mol. Endocrinol., 15(11), 1971-82; and Young et al., (2000), J. Exp. Med., 191(9), 1535-1544); Caspase-4 and Caspase-8 (Annaud et al., (1999)).
(2001)) also suffer from synthetic complexity / high manufacturing cost due to the complex core and accompanying low water solubility.

Method used

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  • Cyclic urea compounds as granzyme b inhibitors
  • Cyclic urea compounds as granzyme b inhibitors
  • Cyclic urea compounds as granzyme b inhibitors

Examples

Experimental program
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examples

Synthetic Intermediates

[0342]The following is a description of synthetic intermediates (I-1 to I-4) useful for making representative compounds of the invention.

[0343]Intermediate I-1

(S)-Dibenzyl 2-oxoimidazolidine-1,5-dicarboxylate (I-1)

[0344](S)-(-)-1-Z-2-Oxo-5-imidazolidinecarboxylic acid (2.5 g, 9.461 mmol, 1 eq.), para-toluenesulfonic acid (360 mg, 1.892 mmol, 0.2 eq.) and benzyl alcohol (2.39 mL, 23.12 mmol, 2.4 eq.) were dissolved in toluene (25 mL) in a round bottom flask equipped with a Dean-stark apparatus and a condenser. The reaction was heated to reflux for 24 hrs and then allowed to come to RT. It was then washed with a saturated solution of NaHCO3 solution (1×25 mL) and the aqueous layer was re-extracted with ethyl acetate (1×25 mL). The combined organic layers were dried over Na2SO4 and concentrated. The product was then purified by column chromatography using 15% to 70% ethyl acetate in hexanes as the eluent to give (S)-dibenzyl 2-oxoimidazolidine-1,5-dicarboxylate (...

example c1

4-(((2S,3S)-1-((2-((S)-5-(((2H-Tetrazol-5-yl)methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-2-oxoethyl)amino)-3-methyl-1-oxopentan-2-yl)amino)-4-oxobutanoic acid

[0353]A solution of I-2 (100 mg, 0.282 mmol, 1 eq.) in anhydrous THF (2 mL) was cooled to −50° C. under N2. Potassium tert-butoxide (31.6 mg, 0.282 mmol, 1 eq.) was then added, followed by Boc-glycine N-hydroxysuccinimide ester (76.7 mg, 0.282 mmol, 1 eq.) and the reaction mixture was slowly allowed to warm up to −10° C. and it was stirred at that temperature for 1 h. Analysis of the reaction mixture by TLC showed the presence of starting material left. The reaction mixture was cooled to −50° C. and potassium tert-butoxide (31.6 mg, 0.282 mmol, 1 eq.), followed by Boc-glycine N-hydroxysuccinimide ester (76.7 mg, 0.282 mmol, 1 eq.) were added and the reaction mixture was slowly allowed to warm up to −10° C. and it was stirred at that temperature for 1 h. TLC showed disappearance of the starting material. The reaction mixture was a...

example c2

4-(((2S,3S)-1-((2-((S)-5-(((2H-TETRAZOL-5-YL)METHYL)CARBAMOYL)-3-CYCLOHEXYL-2-OXOIMIDAZOLIDIN-1-YL)-2-OXOETHYL)AMINO)-3-METHYL-1-OXOPENTAN-2-YL)AMINO)-4-OXOBUTANOIC ACID

[0358]A solution of I-3 (220 mg, 0.733 mmol, 1 eq.) in anhydrous THF (15 mL) was cooled to −50° C. under N2. Potassium tert-butoxide (98 mg, 0.880 mmol, 1.2 eq.) was then added, followed by Boc-glycine N-hydroxysuccinimide ester (240 mg, 0.880 mmol, 1.2 eq.) and the reaction mixture was slowly allowed to warm up to −10° C. and it was stirred at that temperature for 1 h. Analysis of the reaction mixture by TLC showed the presence of starting material left. The reaction mixture was cooled to −50° C. and potassium tert-butoxide (25 mg, 0.219 mmol, 0.25 eq.), followed by Boc-glycine N-hydroxysuccinimide ester (60 mg, 0.219 mmol, 0.25 eq.) were added and the reaction mixture was slowly allowed to warm up to −10° C. and it was stirred at that temperature for 1 h. TLC showed disappearance of the starting material. The react...

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Abstract

Cyclic urea compounds as Granzyme B inhibitors, compositions that include the compounds, and methods for using the compounds. Methods for treating cutaneous scleroderma, epidermolysis bullosa, radiation dermatitis, alopecia areata, and discoid lupus erythematosus are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Application No. 62 / 032,479, filed Aug. 1, 2014, which application is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention disclosure relates generally to agents for treating diseases, disorders, and conditions treatable by inhibiting Granzyme B, and more specifically to cyclic ureas compounds that are inhibitors of Granzyme B.BACKGROUND OF THE INVENTION[0003]Granzyme B is a pro-apoptotic serine protease found in the granules of cytotoxic lymphocytes (CTL) and natural killer (NK) cells. Granzyme B is released towards target cells, along with the pore-forming protein, perforin, resulting in its perforin-dependent internalization into the cytoplasm and subsequent induction of apoptosis (see, for e.g., Medema et al., Eur. J. Immunol. 27:3492-3498, 1997). However, during aging, inflammation and chronic disease, Granzyme B can also be expressed ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61L2/10A61M39/18
CPCA61L2/10A61M39/18A61M2039/167A61L2202/14A61L2202/24C07K5/06026C07K5/0808A61K38/00A61P17/00A61P17/02A61P17/14A61P43/00A61P9/00A61P9/10A61P9/14
Inventor CAMERON, DALE R.
Owner VIDA THERAPEUTICS
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