- Fine-tuning water exchange on GdIII poly(amino carboxylates) by modulation of steric crowding
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In the objective of optimizing water exchange rate on stable, nine-coordinate, monohydrated GdIII poly(amino carboxylate) complexes, we have prepared monopropionate derivatives of DOTA4- (DO3A-Nprop4-) and DTPA5- (DTTA-Nprop5-). A novel ligand, EPTPA-BAA3-, the bisamylamide derivative of ethylenepropylenetriaminepentaacetate (EPTPA5-) was also synthesized. A variable temperature 17O NMR study has been performed on their GdIII complexes, which, for [Gd(DTTA-Nprop)(H2O)] 2- and [Gd(EPTPA-BAA)(H2O)] has been combined with multiple field EPR and NMRD measurements. The water exchange rates, k ex298, are 8.0 × 107 s-1, 6.1 × 107 s-1 and 5.7 × 107 s -1 for [Gd(DTTA-Nprop)(H2O)]2-, [Gd(DO3A-Nprop)(H2O)]- and [Gd(EPTPA-BAA)(H 2O)], respectively, all in the narrow optimal range to attain maximum proton relaxivities, provided the other parameters (electronic relaxation and rotation) are also optimized. The substitution of an acetate with a propionate arm in DTPA5- or DOTA4- induces increased steric compression around the water binding site and thus leads to an accelerated water exchange on the GdIII complex. The kex values on the propionate complexes are, however, lower than those obtained for [Gd(EPTPA)(H2O)]2- and [Gd(TRITA)(H2O)] - which contain one additional CH2 unit in the amine backbone as compared to the parent [Gd(DTPA)(H2O)]2- and [Gd(DOTA)(H2O)]-. In addition to their optimal water exchange rate, [Gd(DTTA-Nprop)(H2O)]2- has, and [Gd(DO3A-Nprop)(H2O)]- is expected to have sufficient thermodynamic stability. These properties together make them prime candidates for the development of high relaxivity, macromolecular MRI contrast agents. The Royal Society of Chemistry 2005.
- Jaszberenyi, Zoltan,Sour, Angelique,Toth, Eva,Benmelouka, Meriem,Merbach, Andre E.
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- PYRROLIDINE COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
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Compounds which modulate the CB2 receptor are disclosed. Compounds according to the invention bind to and are agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
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Page/Page column 129
(2010/08/04)
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- Thrombin inhibitors
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Novel five-membered heterocyclic amidines, their preparation and use as competitive inhibitors of trypsin-like serine proteases, especially thrombin and kininogenases such as kallikrein. Pharmaceutical compositions which contain the compounds as active ingredients, and use of the compounds as thrombin inhibitors, anticoagulants and antiinflammatory agents.
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Page column 29
(2010/02/06)
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- Design, synthesis and antimalarial activity of novel, quinoline-based, zinc metallo-aminopeptidase inhibitors
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PfA-M1, a neutral zinc aminopeptidase of Plasmodium falciparum, is a new potential target for the discovery of antimalarials. The design and synthesis of a library of 45 quinoline-based inhibitors of PfA-M1 is reported. The best inhibitor displays an IC50 of 854 nM. The antimalarial activity on a CQ-resistant strain and the specificity towards mammalian aminopeptidase N are also discussed.
- Flipo, Marian,Florent, Isabelle,Grellier, Philippe,Sergheraert, Christian,Deprez-Poulain, Rebecca
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p. 2659 - 2662
(2007/10/03)
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- BENZAZEPINE-, BENZOXAZEPINE- AND BENZOTHIAZEPINE-N-ACETIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds with neutral endopeptidase (NEP) inhibitory activity corresponding to the formula I STR1 in which R 1 is a lower alkoxy-lower-alkyl group whose lower alkoxy radical is substituted by a lower alkoxy group, or a phenyl-lower-alkyl or phenyloxy-lower-alkyl group which can optionally be substituted in the phenyl ring by lower alkyl, lower alkoxy or halogen, or a naphthyl-lower-alkyl group, A is CH 2, O or S,R 2 is hydrogen or halogen,R. sup.3 is hydrogen or halogen,R 4 is hydrogen or a group forming a biolabile ester, andR 5 is hydrogen or a group forming a biolabile ester, and the physiologically acceptable acid addition salts thereof.
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- 2-alkenylene-thieno-1,2-thiazole derivatives with lipid-lowering activity
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The invention relates to new thieno-1,2-thiazole derivatives of the formula STR1 wherein A, with the two carbon atoms of the thiazole ring, forms a group of the formula STR2 and the broken line indicates the double bond present in the thieno structures of the formulae IIa and IIb, n denotes the integer 2, 3 or 4, R denotes hydrogen or lower alkyl, R1 denotes hydrogen, lower alkyl, halogen, trifluoromethyl, lower alkoxy or lower alkylthio and R2 denotes hydrogen, lower alkyl or halogen; and the pharmaceutically acceptable salts of compounds of the formula I wherein R denotes hydrogen, a process for their preparation, pharmaceutical products containing these compounds, and their use in medicaments. The compounds of the formula I and salts thereof have a lipid-lowering action.
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