147269-63-4Relevant articles and documents
Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
-
Page column 60, (2010/02/05)
Aminoguanidine and alkoxyguanidine compounds are described, including compounds of the Formula VII: wherein X is O or NR9and Het, R1, R7, R8, R12-R15, Ra, Rb, Rc, Z, and n are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin. Also described are methods for preparing such compounds. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.
Pyridone-based peptidomimetic inhibitors of interleukin-1β-converting enzyme (ICE)
Semple, Graeme,Ashworth, Doreen M.,Baker, Graham R.,Batt, Andrzej R.,Baxter, Andrew J.,Benzies, David W.M.,Elliot, Lucy H.,Evans, D. Michael,Franklin, Richard J.,Hudson, Peter,Jenkins, Paul D.,Pitt, Gary R.,Rooker, David P.,Sheppard, Andrew,Szelke, Michael,Yamamoto, Satoshi,Isomura, Yasuo
, p. 1337 - 1342 (2007/10/03)
New potent, reversible inhibitors of recombinant human Interleukin-1 β-converting enzyme (ICE, caspase-1) with significantly reduced peptide character are described. The compounds were designed by incorporation of pyridone and pyrimidone heterocyclic replacements for the P2-P3 amino acids of the native substrate and were optimised by manipulation of peripheral alkyl and aryl substituents.
Nonpeptidic inhibitors of human leukocyte elastase. 2. Design, synthesis, and in vitro activity of a series of 3-amino-6-arylopyridin-2-one trifluoromethyl ketones
Damewood Jr.,Edwards,Feeney,Gomes,Steelman,Tuthill,Williams,Warner,Woolson,Wolanin,Veale
, p. 3303 - 3312 (2007/10/02)
A series of potent nonpeptidic inhibitors of the enzyme human leukocyte elastase (HLE) is reported. These inhibitors contain a 3-amino-2-pyridone ring as a central template in which the pyridone carbonyl and 3-position NH group are thought to form important hydrogen bonding interactions with the Val-216 residue of HLE. Substitution of the 6-position of the pyridone ring by various alkyl and aryl groups was found to afford increases in the in vitro potency of these inhibitors. A 6-position phenyl group, compound 10f, was found to result in a large increase in binding affinity, which was not obtained when the phenyl group was placed in either the 4- or 5-position of the molecule. Compound 10f was found to have good selectivity for HLE over other proteolytic enzymes, with the exception of bovine pancreatic chymotrypsin (BPC). Substitution of the 6-phenyl group in these molecules was found to decrease binding affinity for BPC without adversely affecting affinity for HLE.
