18 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY The chromatographic methods suffer the disadvantage that the retention time is lin early related to the partition coefficient,i.e.for a doubling of the LogP,there is a tenfold increase in the retention.This often requires different length columns to be used,short ones for high LogP values and long ones for low values. Relationships between Log P and activity The partition coefficient is also a ver useful parameter that may be ased in combination with the pKa predict the distributior of a dru ound in a biol such as absorption,excretion and penetration into the CNS may be related to the Log P value of a drug.Drugs should be des ned with the lowest possible Log P,to reduce toxicity,non specific binding,increase ease of formulation and bioavailability. Relationships between LogP and activit e often found in stru 1 、H leads value for the log pf a desired activity o selectiv e distribution.Relatio of the ypes are generated using egression ctivity with measured partition coefficients. Activity m log p-clog p)2-k(parabolic) Activity=m log P-c(blog P+1)-k(rectilinear)(where m,k and c are co The best way of relating LogP,pKa and other physico-chemical properties to biologica activity is using multivariate techniques such as Principal Components Analysis and Partia Least Squares regression DISSOCIATION CONSTANTS The dissociation constant is one of the most important characteristics of a pharmaceutical compound.Majority of drugs are weak acids or weak bases and like acetic acid or ammonia. ater to form conjugate pairs.The pKa or Dissociation constant'is a measure an acid or a base and is sometin s called the acic uty const nt or the ioni tion constar a nume stance,or t of that on as the equilibrium constant. Weak acid drug Water H2O*+Weak base drug anion- acid base conjugate acid conjugate base Weak base drug+Water OH- HWeak base drug Let us consider equation for the protolysis of water by an acidic drug (HA). HA+HO H0+A At equilibrium,the velocity of the reaction proceeding to the ionized components(k)is equal to the velocity of the reaction resulting in the unionized HA and HO(). 18 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE3-1.PM5 The chromatographic methods suffer the disadvantage that the retention time is lin￾early related to the partition coefficient, i.e. for a doubling of the LogP, there is a tenfold increase in the retention. This often requires different length columns to be used, short ones for high LogP values and long ones for low values. Relationships between Log P and activity The partition coefficient is also a very useful parameter that may be used in combination with the pKa to predict the distribution of a drug compound in a biological system. Factors such as absorption, excretion and penetration into the CNS may be related to the Log P value of a drug. Drugs should be designed with the lowest possible Log P, to reduce toxicity, non￾specific binding, increase ease of formulation and bioavailability. Relationships between Log P and activity are often found in series where structural modifications have not significantly affected the pKa values. Hansch in 1964 showed that these relationships were often parabolic hence the relationship often leads to an optimum value for the log P for a desired activity or selective distribution. Relationships of the following types are generated using regression analysis to correlate observed biological activity with measured partition coefficients. Activity = m log P + k′ (linear) Activity = m log P – c(log P)2 – k(parabolic) Activity = m log P – c(blog P +1) – k(rectilinear) (where m, k and c are constants) The best way of relating LogP, pKa and other physico-chemical properties to biological activity is using multivariate techniques such as Principal Components Analysis and Partial Least Squares regression.
   The dissociation constant is one of the most important characteristics of a pharmaceutical compound. Majority of drugs are weak acids or weak bases and like acetic acid or ammonia, they react with water to form conjugate pairs. The pKa or ‘Dissociation constant’ is a measure of the strength of an acid or a base and is sometimes called the acidity constant or the ioniza￾tion constant. It is a numerical representative of the relative proton transfer for that sub￾stance, or the likelihood of that compound donating a proton. It is calculated in the same fashion as the equilibrium constant. Weak acid drug + Water H3O+ + Weak base drug anion– acid base conjugate acid conjugate base Weak base drug + Water OH– + H+ Weak base drug base acid conjugate base conjugate acid Let us consider equation for the protolysis of water by an acidic drug (HA). HA + H2O H3O+ + A– At equilibrium, the velocity of the reaction proceeding to the ionized components (k1) is equal to the velocity of the reaction resulting in the unionized HA and H2O (k2)