Class III compound

From the discussion of compounds above, it can be seen that Class III elec-trophysiological activity can be elicited with a wide variety of structural types. At first glance there do not seem to be specific requirements to produce active compounds. When the structures of the selective Class III compounds (that is, concentration-dependent prolongation of APD with minimal (< 5 %) inhibition of F ax are compared, a pattern emerges which can be used to define structure activity requirements. A general structure for a selective Class III agent is presented in Figure 2.3. 

Classes I, III, and IV all involve transmembrane ion channels Classes I and III involve Na+ channels. Class I compounds are designed to block cardiac Na channels in a voltage-dependent manner, similar to local anesthetics. Not surprisingly, many of these Class I agents are either local anesthetics or are structurally based on local anesthetics. Class I compounds include procainamide (7.15), disopyramide (7.16), amiodarone (7.17), lido-caine (7.5), tocainide (7.18), mexiletine (7.19), and flecainide (7.20). The majority of these compounds possess two or three of the fundamental structural building blocks found within local anesthetics. Propranolol (7.21) is the prototypic Class II agent. Class III compounds include molecules that block outward K channels, such as sotalol (7.22) and dofetilide (7.23), and molecules that enhance an inward Na current, such as... 

The literature references sodium caprate (CIO) being used as a permeation enhancer in both preclinical (Ishizawa et al. 1987) and clinical studies of Class III compounds (Lindmark et al. 1997). Permeation data from in situ rodent studies calculate tight junctions opening after CIO dosing which is consistent with the cross-sectional diameter of ASOs (Ma et al. 1992 Tsutsumi et al. 2003). The work of Raoof et al. demonstrated in the pig and dog, that the use of permeation enhancers, notably CIO, represents an attractive strategy to enhance the oral delivery of ASO molecules (Raoof et al. 2002, 2004). In Fig. 12.3 the pharmacokinetic of an orally administered ASO utilizing sodium caprate as permeation enhancer is illustrated. 

For the sake of completeness one should also add that Blume and Schug [232] suggested that Class III compounds (high solubility and low permeability) are better candidates for a waiver of bioavailabihty and bioequivalence studies since bioavailability is not so much dependent on the formulation characteristics as on the permeability of the compound. Finally, the recent extension [233] of BCS toward disposition principles underlines the importance of using the... 

In class I mixed valence species, electron transitions between sites are energetically difficnlt to accomplish. In the sohd state, these materials are generally insnlators. However, with class II and class III compounds, electron transfer becomes much easier so that conducting and superconducting materials are obtained (see Sulfur Organic Polysulfanes). 

The main spectroscopic consequence of the combined action of electron transfer and vibronic interaction is the occurrence of the so-called electron transfer optical absorption (intervalence band), which is shown by the arrows in Fig. 10. The shape and intensity of the intervalence band in the PKS model is defined by the ratio t /(v /cu). In the case of weak transfer the Franck-Condon transitions are almost forbidden, and at the same time, the Stokes shift can be significant. Therefore the MV dimers of Class I are expected to exhibit weak and wide intervalence bands. On the contrary, in the Class III compounds the Franck-Condon transition is allowed, and the Stokes shift is zero. For this reason, intervalence optical bands in delocalized MV dimers are strong and narrow. When the extra electron jumps over the spin cores in a multielecton MV dimer d" — > 1) [85-87] we are dealing with... 

All chemicals tested were classified according to the scheme shewn in Table l. Class I compounds are inactive while Class II materials are good toxicants but do not have the required delayed toxicity. Class III compounds have delayed action, but the concentration range of their activity is too narrow. The type of activity we are looking for in a toxicant is exemplified by a Class IV or V response, i.e., it exhibits delayed toxicity over a wide range of concentrations. 

This suggests that DCS Class I compounds are those with high solubility and high permeability based on kinetic solubility and PAMPA or Caco-2 analyses. Class II compounds are those associated with high permeability and by medium or low solubility while Class III compounds are associated with high solubility and medium or low permeability. Class IV materials have both low solubility and low permeability (Figure 4). 

Robin and Day classification of the degree of electronic coupling in MV compounds, (a) Class I compounds are completely localized, (b) Class II compounds are weakly coupled, and (c) Class III compounds are delocalized. 

Schematic iiiustration of ciass I, ciass II, and class III compound states...

To differentiate between class n and class III compounds, the peak width at half height of the IT band, AVi/2, is measured. If Avi/2 a 48.06(v , ) the compound can be considered class II. If Avi/2 < 48.06(v ) , the compound is considered to be class III. The solvent dependence of the IT band can also be used as an indication of the extent of delocalization. Since class ni compounds do not have a change in dipole upon intervalence charge transfer, the IT bands of class III compounds do not exhibit a strong solvent dependence. A thud method of determining the class of a compound is by the intensity of the IT band. 

Class III compounds posses a completely delocalized structure where the two centres are completely equivalent, while Class II compounds can exhibit temperature dependent localisation effects. The low energy transition, Eopt, usually called Intervalence Transition (IT), confers to these complex their color. In magnetic systems, each spin state does follow the vibronic behavior shown in Scheme 3 according to the equation ... 

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