- NUCLEOSIDE PHOSPHONATE DERIVATIVES USEFUL IN THE TREATMENT OF HIV INFECTIONS
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The present invention relates to a method of treating HIV infections by administering a nucleoside phosphonate derivative represented by formula (I).
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Page/Page column 47
(2008/06/13)
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- Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
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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.
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Page column 49-50
(2010/02/05)
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- Inactivation of γ-Aminobutyric Acid Aminotransferase by (S,E)-4-Amino-5-fluoropent-2-enoic Acid and Effect on the Enzyme of (E)-3-(1-Aminocyclopropyl)-2-propenoic Acid
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(S,E)-4-Amino-5-fluoropent-2-enoic acid (6) is synthesized in six steps starting from the known γ-aminobutyric acid aminotransferase (γ-Abu-T) inactivator, (S)-4-amino-5-fluoropentanoic acid (1).Compound 6 is a mechanism-based inactivator of γ-Abu-T: time-dependent inactivation is saturable and protected by substrate; thiols do not protect the enzyme from inactivation; no enzyme activity returns upon dialysis.This compound (6) binds 50 times more tightly to γ-Abu-T than does the saturated analogue (1).No transamination of 6 occurs prior to inactivation.However, five molecules of 6 are required to inactivate the enzyme with concomitant release of five fluoride ions.Therefore, four molecules are being converted to product for each inactivation event. (E)-3-(1-Aminocyclopropyl)-2-propenoic acid is synthesized in seven steps from 1-aminocyclopropanecarboxylic acid.It is prepared as a cyclopropyl derivative of the proposed intermediate in the inactivation of γ-Abu-T by 6.The cyclopropyl derivative, however, is a noncompetitive inhibitor and does not inactivate the enzyme.This study shows the usefulness and hazards of incorporation of a trans double bond into potential γ-Abu-T inactivators.
- Silverman, Richard B.,Invergo, Benedict J.,Mathew, Jacob
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p. 1840 - 1846
(2007/10/02)
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