1268810-17-8Relevant articles and documents
The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K
Mons, Elma,Jansen, Ineke D. C.,Loboda, Jure,Van Doodewaerd, Bjorn R.,Hermans, Jill,Verdoes, Martijn,Van Boeckel, Constant A. A.,Van Veelen, Peter A.,Turk, Boris,Ovaa, Huib
supporting information, p. 3507 - 3514 (2019/02/26)
Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation (kinact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.
CATHEPSIN INHIBITORS
-
Paragraph 00136, (2019/06/23)
This invention relates to compounds that are useful as inhibitors, in particular as inhibitors of Cathepsin K (CatK), and to a method of inhibiting cathepsin activity, comprising administering a compound or formulation comprising a compound according to the invention.
Technological synthesis method of 1-amino cyclopropyl acetylene
-
Paragraph 0050; 0051; 0052; 0053, (2016/10/09)
The invention discloses a technological synthesis method of 1-amino cyclopropyl acetylene. The method includes: taking compound 1 as the starting material, and carrying out oxidation, Corey-Fuchs reaction, and amino protection group removal so as to obtain the 1-amino cyclopropyl acetylene. The reagents and raw materials used by the method provided by the invention are cheap and easily available, and low in cost. With the advantages of high reaction safety, simple operation and high yield, the method is suitable for industrial scale-up production. (with the synthesis process shown as the specification).
2,4-DIOXO-QUINAZOLINE-6-SULFONAMIDE DERIVATIVES AS INHIBITORS OF PARG
-
Page/Page column 102; 227, (2016/07/05)
The present invention relates to compounds of formula I that function as inhibitors of PARG (Poly ADP-ribose glycohydrolase) enzyme activity wherein R1a, R1b, R1c, R1d, R1e, W, X1, X2, X3, X4, X5, X6, X7, c are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which PARG activity is implicated.
Productive syntheses of 1-ethynylcyclopropylamine and 1- ethynylcyclobutylamine
Kozhushkov, Sergei I.,Wagner-Gillen, Karsten,Khlebnikov, Alexander F.,Demeijere, Armin
experimental part, p. 3967 - 3973 (2011/02/22)
The new 1,1-dimethylpropargylamine surrogates, 1-ethynylcyclopropylamine (3) and 1-ethynylcyclobutylamine (5), were prepared as hydrochlorides from cyclopropylacetylene and 6-chlorohex-1-yne in overall yields of 39 and 25%, respectively, on a scale of up to 300 mmol. The amine 3 was converted into the new ethynyl-extended 1-aminocyclopropanecarboxylic acid 4, and both the amine 3 as well as the amino acid 4 were made available as their N-Fmoc-protected derivatives. Georg Thieme Verlag Stuttgart - New York.
