- Structure-activity relationships of novel azomethine prodrugs of the histamine H3-receptor agonist (R)-α-methylhistamine: From alkylaryl to substituted diaryl derivatives
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This study was performed on the basis of recently developed prodrugs of the histamine H3-receptor agonist (R)-α-methylhistamine (1) to determine structure-activity relationships of azomethine prodrugs of 1, in which the primary amine functionality is bioreversibly linked to aromatic ketones. Therefore, the pro-moiety was systematically altered from alkylaryl over benzylaryl to diaryl substitution. Those compounds that emerged to be stable enough during preparation were tested for their in vitro hydrolysis rates. Apparently, bulky alkyl residues were capable of preventing previously observed intramolecular cyclization, but the obtained azomethines 12 a-c were far too unstable to serve as prodrugs. However, the benzylaryl imines 12d, e were stable compounds, but 12d decomposed too rapidly under in vitro conditions. Distinctly greater stability was provided by diaryl pro-moieties, even if strongly electron-withdrawing functionalities were introduced. Selected compounds were also tested in vivo following p.o. application to mice. Particularly the trifluoromethyl substituted imine 12i proved to be highly effective as stability and rate of conversion were well-balanced, so that brain penetration of 1 was strikingly facilitated. Thus 12i, a highly potent azomethine prodrug, may serve as an important pharmacological tool and, possibly, a therapeutic agent.
- Krause,Rouleau,Stark,Garbarg,Schwartz,Schunack
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p. 720 - 726
(2007/10/03)
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- The conformational properties of some phenyl esters. Molecular orbital and nuclear magnetic resonance studies
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Extensive, geometry-optimized, STO-3G MO computations on phenyl formate imply a strongly nonplanar Z conformer (C=O bond cis to the phenyl group) at ambient temperatures.The internal barrier to rotation about the C(1)-O bond in this conformer is computed as V/kJ mol-1=(-5.17+/-0.27)sin2θ - (2.42+/-0.27)sin22θ, θ being zero for the planar conformer; the twofold is nearly twice as large as the fourfold component.The expectation value of θ is 58 deg at 300 K.The spin-spin coupling constants over six bonds between (13)C and (19)F nuclei in 4-fluorophenyl formate, acetate, propionate, and isobutyrate, as well as in the 2,6-dichloro-4-fluorophenyl acetate, are adduced as evidence for nonplanar conformers of these molecules.The magnitudes of these six-bond coupling constants are consistent with internal barriers to rotation about the C(1)-O bonds, which are similar in magnitude to those given by the computations on the Z conformer of phenyl formate.The energies of the planar and nonplanar E conformers, as well as the interconversion energies for EZ isomerization, are computed.Small amounts of the nonplanar E conformer are predicted at ambient temperatures.The (13)C chemical shifts and the one-bond (13)C, (19)F coupling constants are consistent, respectively, with only minor variations in the conformational behavior of the ester moieties caused by the fluorine substituent and by changes in the structures of these moieties themselves.
- Schaefer, Ted,Penner, Glenn H.
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p. 2175 - 2178
(2007/10/02)
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