Permeability chemistry control

Aqueous solubility, potency and permeability are three factors under medicinal chemistry control that must be optimized to achieve a compound with acceptable oral absorption. Typically, a lead (chemistry starting point) is deficient in all three parameters. The inter-relationships of these three parameters has been described in a series of publications from Pfizer researchers [7, 8]. Figure 9.1 depicts graphically the minimum acceptable solubility as a function of projected clinical potency and intestinal permeability. A minimum thermodynamic aqueous solubility of 52... 

Bolton E. W., Lasaga A. C., and Rye D. M. (1999) Long-term flow/chemistry feedback in a porous medium with heterogeneous permeability kinetic control of dissolution and precipitation. Am. J. Sci. 299, 1-68. 

Chemistry control of intestinal permeability via passive trani-cellular processes is poor. The good news is that, in general, poor permeability is not a problem in combinatorial libraries. One really has to go out of one s way to introduce enough polar functionality in a combinatorial compound to... 

Chemistry control of aqueous solubility is poor because, except for a few very specific exceptions, chemistry SAR is blunt. In this respect, control of solubility like that of permeability is poor. Solubility due to excessive lipophilicity... 

Chemistry control of intestinal permeability is poor. The good news is that, in general, poor permeability is not a problem in combinatorial libraries. One really has to go out of one s way to introduce enough polar functionality in a combinatorial compound to make a compound impermeable via passive rran -cellular processes (the most common absorptive pathway). The bad news is that if a compound has poor intestinal permeability there is virtually nothing to fix the problem in terms of pharmaceutical formulation technology. Chemistry control of intestinal permeability is poor because, except for a few very specific exceptions, chemistry SAR is blunt. 

A comparison of Tables 1 and 5 reveals the novelty of our multicomponent approach to capsule formation and permeability control. Of the existing chemistries in Table 5 only capsules 3,4, and 5 conform to our recipe (technol-... 

Strong et al. 1996). Studies in these animals indicate that exposure to aluminum can affect permeability of the blood-brain barrier, cholinergic activity, signal transduction pathways, lipid peroxidation, and glucose metabolism, as well as interfere with metabolism of essential trace elements (e.g., iron) because of similar coordination chemistries and consequent competitive interactions. Signal pathways are important in all cells and control differentiation and proliferation, neurotransmitter release,... 

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