Lipophilicity in PK design: methyl, ethyl, futile

Lipophilicity, often expressed as distribution coefficients (log D) in octanol/water, is an important physicochemical parameter influencing processes such as oral absorption, brain uptake and various pharmacokinetic (PK) properties. Increasing log D values increases oral absorption, plasma protein binding and volume of distribution. However, more lipophilic compounds also become more vulnerable to P450 metabolism, leading to higher clearance. Molecular size and hydrogen bonding capacity are two other properties often considered as important for membrane permeation and pharmacokinetics. Interrelationships among these physicochemical properties are discussed. Increasing size (molecular weight) often gives higher potency, but inevitably also leads to either higher lipophilicity, and hence poorer dissolution/solubility, or to more hydrogen bonding capacity, which limits oral absorption. Differences in optimal properties between gastrointestinal absorption and uptake into the brain are addressed. Special attention is given to the desired lipophilicity of CNS drugs. In examples using h3/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-blockers, Ca channel antagonists and peptidic renin inhibitors we will demonstrate how potency and pharmacokinetic properties need to be balanced.     

Crystal Structures of [Ni(Phen)(i‐Bu2PS2)2] and [Ni(Phen)3](i‐Bu2PS2)2 Complexes and Interaction between Coordinated 1,10‐Phenanthroline Molecules

Single crystals of [Ni(Phen)(ih8/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0">Bu₂PS₂)₂] (I) and [Ni(Phen)₃](ih8/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0">Bu₂PS₂)₂ (III) compounds were grown, and their structures were determined by Xh8/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0">ray diffraction analysis (CADh8/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0">4 diffractometer, MoK _{h8/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">} radiation, 3336 F _hkl , R = 0.0373 for I and 2575 F _hkl for III). The crystals of complex I have a triclinic unit cell with the following parameters: a = 11.097(1) h8/xxlarge8491.gif" alt="angst" align="MIDDLE" BORDER="0">, b = 14.903(2) h8/xxlarge8491.gif" alt="angst" align="MIDDLE" BORDER="0">, c = 22.650(3)h8/xxlarge8491.gif" alt="angst" align="MIDDLE" BORDER="0">; h8/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0"> = 75.18(1)°, h8/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0"> = 80.50(1)°, h8/xxlarge947.gif" alt="gamma" align="MIDDLE" BORDER="0"> = 75.07(1)°, V = 3479.2(7)h8/xxlarge8491.gif" alt="angst" align="MIDDLE" BORDER="0">³, Z = 4, h8/xxlarge961.gif" alt="rgr" align="MIDDLE" BORDER="0">_calc = 1.255 g/cm³, and space group h8/10947_2004_Article_474369_TeX2GIFIE1.gif" alt=" $$\bar P$$ " align="middle" border="0"> 1; the crystals of III have a monoclinic unit cell with the following parameters: a = 19.010(3)h8/xxlarge8491.gif" alt="angst" align="MIDDLE" BORDER="0">, b = 15.481(1) h8/xxlarge8491.gif" alt="angst" align="MIDDLE" BORDER="0">, c = 17.940(3)h8/xxlarge8491.gif" alt="angst" align="MIDDLE" BORDER="0">; h8/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0"> = 97.58(1)°, V = 5233.5(12)h8/xxlarge8491.gif" alt="angst" align="MIDDLE" BORDER="0">³, Z = 4, h8/xxlarge961.gif" alt="rgr" align="MIDDLE" BORDER="0">_calc = 1.292 g/cm³, and space group C2/c. The structure of complex I is built from mononuclear molecules, and the structure of III, from [Ni(Phen)₃]²⁺ complex cations and ih8/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0"> Bu₂PS₂ ^- outerh8/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0">sphere anions. The NiN₂S₄ coordination polyhedra in the structure of I and NiN₆ in the structure of III are distorted octahedra. Based on structural data, the interaction between the coordinated Phen molecules of complexes I, [Ni(Phen)₂(ih8/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0">Bu₂PS₂)](ih8/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0">Bu₂PS₂) (II), and III is considered, as well as the packing modes of these complexes.     

Emission,Emissionslebensdauer und Absorption von [Cr urea6]X3-Einkristallen

Emission and absorption polarization spectra as well as emission lifetimes between room temperature and 5 °K have been measured of [Cr urea₆]X₃ single crystals, where X stands for ClO ₄ ^– , J^–, NO ₃ ^– , Br^–, Cl^–, F^–, and X₃ for JSO ₄ ^3– . The strong temperature dependence of the fluorescence/phosphorescence-ratios, and of the emission lifetimes is discussed. The differences between the spectra as well as the emission lifetimes of the various salts can be attributed to an anion dependent trigonal perturbation.

Die Autoren danken dem Verband der Chemischen Industrie für finanzielle Unterstützung dieser Arbeit.     

Dynamics of superionic Rb3H(SeO4)2 single crystals studied by H and Rb spin-lattice relaxation

The ¹H and ⁸⁷Rb spin-lattice relaxation and spin-spin relaxation times in superionic Rb₃H(SeO₄)₂ single crystals grown by the slow evaporation method were measured over the temperature range 160-450 K. The temperature dependencies of the ¹H T₁, T_1ρ, and T₂ are measured. In the ferroelastic phase, T₁ differs from T_1ρ, which is in turn different from T₂, although these three relaxation times converge to similar values near 410 K. This transition seems to occur at temperature which is about 40 K lower than the superionic transition temperature. The observation of liquid-like values of the ¹H T₁, T_1ρ, and T₂ in the high temperature is compatible with the phase being superionic, indicating that the destruction and reconstruction of hydrogen bonds does indeed occur at high temperature. In addition, the ⁸⁷Rb T₁ and T₂ values at high temperature were similar (on the order of milliseconds), a trend that was also observed for ¹H T₁ and T₂. This behavior is expected for most hopping-type ionic conductors, and could be attributed to interactions between the mobile ions and the neighboring group ions within the crystal. The motion giving rise to this liquid-like behavior is related to the superionic motion.     

4,4′-Dipyridyl and 2,2′-dipyridyl complexes of rare-earth perchlorates

4,4h5415/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-Dipyridyl and 2,2h5415/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-dipyridyl complexes of rare-earth perchlorates of the formulaLn(4-dipy)₈(ClO₄)₃HClO₄ · 4H₂O (Ln=La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Yb, Lu, Y, 4-dipy=4,4h5415/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-dipyridyl) andLn(2-dipy)₃(ClO₄)₃ · 6H₂O (Ln=Pr, Sm, Eu, Gd, Tb, Dy, Ho, Er, Yb, Lu, Y, 2-dipy = 2,2h5415/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-dipyridyl) have been synthesized. The IR spectra of these compounds and other physical properties are discussed.<hr>

4,4h5415/xhuge8242.gif" alt="prime" align="BASELINE" BORDER="0">-Dipyridyl- und 2,2h5415/xhuge8242.gif" alt="prime" align="BASELINE" BORDER="0">-Dipyridylkomplexe von Seltenerdmetallperchloraten

Zusammenfassung Es wurden 4,4h5415/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-Dipyridylkomplexe des TypsLn(4-dipy)₈(ClO₄)₃HClO₄ · · 4 H₂O mitLn=La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Yb, Lu, Y und 2,2h5415/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-Dipyridylkomplexe des TypsLn(2-dipy)₃(ClO₄)₃ · 6 H₂O mitLn=Pr, Sm, Eu, Gd, Tb, Dy, Ho, Er, Yb, Lu und Y dargestellt. Die IR-Spektren und andere physikalische Eigenschaften werden diskutiert.

     

Spectroscopic and thermodynamic studies on solvatochromic nickel(II) complexes

Summary The solvatochromic and thermochromic behaviour of a series of mixed Ni(II) complexes with unsubstituted and substituted h5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-diketones and diamines in the solvents 1,2-dichloroethane (DCE), acetonitrile (An), acetone (AC),n-butanol (n-BuOH), formamide (FA), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and pyridine (PY) has been studied and characterized on the basis of electronic spectra. Spectrophotometric methods have been used to evaluate equilibrium constants and their enthalpic and entropic terms for the formation of Ni(h5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-dik)(diam)L ⁺ and Ni(h5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-dik)(diam)L ₂ ⁺ . Increasing donor strength of the donor-solvents (L) and (or) increasing electronwithdrawing parameters of the substituents at the h5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-diketone and the diamine ligands lead to increasing formation constants, paralleled by relative increase in the stability of the five-coordinated species Ni(h5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-dik)(diam)L ⁺. The results are discussed in terms of the extended donor-acceptor concept.On leave of absence from the Faculty of Education, Ain Schams University, Roxy, Cairo, Egypt     

Trace anomaly and chiral symmetry breaking scale in the Nambu and Jona-Lasinio model

Bound state pion production in⁴⁰Ca and¹²⁰Sn nuclei in (p,2p) and (n,d) reactions is investigated. The differential and total cross sections have been obtained. It is shown that the cross sections are determined by the overlap function of the bound states of the nucleon and pion, and as consequence,s-wave part of the pion-nucleus optical potential. The contributions from the nucleons and deuteron distortions are evaluated.The authors would like to express their gratitude to R.A. Eramzhyan, S.N. Gninenko, V.B. Kopeliovich, V.M. Lobashev, B.B. Matveev and E. Oset for very useful and stimulating discussions.     

Vibrational features in inelastic electron tunneling spectra

A theoretical analysis of inelastic electron tunneling spectroscopy (IETS) experiments conducted on molecular junctions is presented, where the second derivative of the current with respect to voltage is usually plotted as a function of applied bias. Within the nonperturbative computational scheme, adequate for arbitrary parameters of the model, we consider the virtual conduction process in the off-resonance region. Here we study the influence of few crucial factors on the IETS spectra: the strength of the vibronic coupling, the phonon energy, and the device working temperature. It was also shown that weak asymmetry in the IETS signal with respect to bias polarity is obtained as a result of strongly asymmetric connection with the electrodes.     

Reactivity of pyrrole pigments. Part 9 MINDO/3 calculations on dipyrrolic partial models of bile pigments

The applicability of the MINDO/3 method is evaluated for calculations on dipyrrolic partial structures of bile pigments. It is shown that this method cannot be used for an accurate conformational analysis. However, when applying the frontier orbital model for reactivity parameters, a good picture of the HOMO and the LUMO distribution can be obtained in this type of molecules.<hr>

Reaktivität von Pyrrolpigmenten, 9. Mitt. MINDO/3-Rechnungen von dipyrrolischen Partialmodellen von Gallenpigmenten

Zusammenfassung Es werden die Einsatzmöglichkeiten von MINDO/3 für den Fall dipyrrolischer Partialstrukturen der Gallenpigmente aufgezeigt. Die Methode ist für eine genaue Konformationsanalyse nicht geeignet. Unter Verwendung der Reaktionsparameter des Frontier-Orbital-Modells läßt sich jedoch ein gutes Bild der HOMO- und LUMO-Verteilung für diesen Verbindungstyp gewinnen.

     

Correction to the Paper - Determination of a Domain in Complex Space by its Automorphism Group

The author offers some corrections to his article which appeared in Vol. 47, No. 3 of this journal.