Leading Edge Predictors for Drug Discovery |

CSLogD ...Introduction |

Definition of Log D Property Data |

Log D is the ratio of the equilibrium concentrations of all species (unionized and ionized) of a molecule in octanol to same species in the water phase at a given temperature, normally 25° C. It differs from LogP in that ionized species are considered as well as the neutral form of the molecule. LogD is defined as: |

- where the sum is over all species and the
subscripts |

Log D Lipophilicity Profile |

The lipophilicity profile becomes quite complex,
even for diprotic compounds. Here we examine a monoprotic base and acid-base-ampholyte
to explain how LogD is computed in these two cases from 14 cases handled
in
The basic equilibrium expression is: HX+ = Xo + H+ ...which exists in two phases. |

The equilibrium dissociation constant, k2 for the octanol phase is commonly known as the ”Scherrer pKa” or “limiting pKa” is not necessary to evaluate. P3 and P4 are partition coefficients with logP3 = logP and P4 for the protonated base. LogD can be expressed with use of P3, P4, and k1 as: |

The rather straight forward form for logD
does not take into consideration ion-pairing, which occur with counterions
present (1, 2). Further, partition coefficients for ionized
species have to be estimated since they are rarely available in reported
logD measurements. In (1). A. Avdeef (1992) Quant.Struct.-Act. Relat. 11, 510; (2).R. Scherrer (2001) “Biolipid pKa Values and the Lipophilicity of Ampholytes and Ion Pairs” in Pharmacokinetic Optimization in Drug Research, Eds. B. Testa, H. van de Waterbeemd, G. Folkers, and R. Guy, Publ. Wily-VCH |

Ampholyte: Acid-Base or Base-Acid |

LogD
can be expressed in a general form for ampholytes. The largest class
covered by The general expression is: |

...where the P terms are partition coefficients of the species with Po having the least number of dissociated hydrogens (e.g., diprotic base, Po goes with the neutral form B, PhX with HB+, Ph2X with H2B++, and Ph3X = 0). Ao, A1, A2, and A3 are various combinations of pKa's with pH whose expressions and number depend upon the type of ampholyte in question (e.g., base-base versus acid-base-base). Acid-Base or Base-Acid Here there are four different species (anion, cation, zwitterion, and neutral), as shown schematically below where k1, k2, k3, k4, and kT are the microconstants |

Also for the apparent dissociation constants, we have: |

Using the expressions for k1, k2, k3, k4, kT, ka1, ka2, and [HX], we have for the expression for logD: |

The general expression for D for AB-BA ampholyte is: |

Using equations (1) - (10) with equation (12), it can be shown that D takes the form involving only aqueous species and their partition coefficients: |

With the assumption that the zwitterion does not enter the octanol phase and ka1 ~ k2, expression (13), becomes: |

It is this expression used within vs Experimental.CSLogD |

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