10596-23-3Relevant articles and documents
Bisphosphonate prodrugs: Synthesis and in vitro evaluation of novel clodronic acid dianhydrides as bioreversible prodrugs of clodronate
Ahlmark, Marko,Veps?l?inen, Jouko,Taipale, Hannu,Niemi, Riku,J?rvinen, Tomi
, p. 1473 - 1476 (1999)
P,P'-Diacetyl, P,P'-dibutyroyl, P,P'-dipivaloyl, and P,P'-dibenzoyl (dichloromethylene)bisphosphonic acid dianhydride disodium salts (2a-d) were synthesized and evaluated as novel bioreversible prodrugs of clodronate. The anhydrides were prepared by reacting anhydrous tetrasodium clodronate with a large excess of the corresponding acid anhydride. The dianhydrides 2a-d alone were more lipophilic than the parent clodronate, as determined by drug partitioning between 1-octanol and phosphate buffer at pH 7.4. They also were stable toward chemical hydrolysis in aqueous solutions (pH 7.4 and 2.0). The half-lives for chemical degradation in a buffer solution at 37 °C varied from 0.7 to 286 h and from 15 to 790 h at pH 2.0 and 7.4, respectively. The dianhydrides 2a,b,d underwent complete enzymatic hydrolysis to clodronate in 80% serum at 37 °C after 1 min, although 2c had a half-life of 3.3 h. The aqueous solubility of clodronate decreased considerably in the presence of Ca2+ ions. This is most probably due to formation of poorly water-soluble chelates, which may also hinder the oral absorption of clodronate. However, Ca2+ ions did not have an effect on the aqueous solubility of clodronic acid dianhydrides, and therefore, these prodrugs may improve oral absorption of the parent drug. In conclusion, these novel dianhydride derivatives may be potentially useful prodrugs of clodronate which, due to their lipophilicity and lack of Ca2+ chelating, increase its bioavailability after oral administration.
Transition state in DNA polymerase β Catalysis: Rate-Limiting chemistry altered by base-pair configuration
Oertell, Keriann,Chamberlain, Brian T.,Wu, Yue,Ferri, Elena,Kashemirov, Boris A.,Beard, William A.,Wilson, Samuel H.,McKenna, Charles E.,Goodman, Myron F.
, p. 1842 - 1848 (2014/04/17)
Kinetics studies of dNTP analogues having pyrophosphate-mimicking β,β-pCXYp leaving groups with variable X and Y substitution reveal striking differences in the chemical transition-state energy for DNA polymerase β that depend on all aspects of base-pairing configurations, including whether the incoming dNTP is a purine or pyrimidine and if base-pairings are right (T*A and G*C) or wrong (T*G and G*T). Br?nsted plots of the catalytic rate constant (log(kpol)) versus pKa4 for the leaving group exhibit linear free energy relationships (LFERs) with negative slopes ranging from -0.6 to -2.0, consistent with chemical rate-determining transition-states in which the active-site adjusts to charge-stabilization demand during chemistry depending on base-pair configuration. The Br?nsted slopes as well as the intercepts differ dramatically and provide the first direct evidence that dNTP base recognition by the enzyme-primer-template complex triggers a conformational change in the catalytic region of the active-site that significantly modifies the rate-determining chemical step.
Tablet with improved bioavailability containing dichloromethylenediphosphonic acid as the active substance
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, (2008/06/13)
The invention concerns tablets with improved bioavailability of the active substance dichloromethylenediphosphonic acid or of a physiologically tolerated salt thereof and with a content of microcrystalline cellulose as a pharmaceutical auxiliary substance, pharmaceutical packs containing these tablets, the use of the active substance dichloromethylenediphosphonic acid together with microcrystalline cellulose for the production of a tablet with improved bioavailability and the process for producing the tablet.
