Quantitative structure-activity relationship lipophilicity

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

Lipophilicity is the measure of the partitioning of a compound between a lipidic and an aqueous phase [1]. The terms lipophilicity and hydrophobicity are often used inconsistently in the literature. Lipophilicity encodes most of the intramolecular forces that can take place between a solute and a solvent. Hydrophobicity is a consequence of attractive forces between nonpolar groups and thereby is a component of lipophilicity [2]. Lipophilicity is one of the most informative physicochemical properties in medicinal chemistry and since long successfully used in quantitative structure-activity relationship (QSAR) studies. Its... 

Dearden,. C. Partitioning and lipophilicity in quantitative structure-activity relationships. Environ. Health Perspect. 1985, 67, 203-228. 

Lewis, D. F., Lake, B. G., Ito, Y., Anzenbacher, P. Quantitative structure-activity relationships (QSARs) within cytochromes P450 2B (CYP2B) subfamily enzymes the importance of lipophilicity for binding and metabolism. Drug Metab. Drug Interact. 

Lipophilicity appears in several Quantitative Structure-Activity Relationships (QSAR) studies [16], emphasizing its importance. Different in vitro assays have been reported to measure lipophilicity from the classical shake-flask technique that still remains the reference for lipophilicity measurements to more actual methodologies. The first procedure is time-consuming, sensitive to impurities and the measurable log Poct range restricted to -3 to 3 [17]. 

GaiUard, P., Carrupt, R A., Testa, B., and Schambel, R (1996) Binding of arylpiper-azines, (aryloxy)propanolamines and tetrahydropyridyl-indoles to the 5-HT1A receptor contribution of the molecular lipophilicity potential to three-dimensional quantitative structure-activity relationship models. J. Med. Chem. 39, 126-134. 

The lipophilic behaviour of organic compounds 1. An updating of the hydrophobic fragmental constant approach. Quantitative Structure-Activity Relationships, 17, 517-536. 

Rekker, R.F., Mannhold, R., Biljoo, G., de Vries, G. and Dross, K. (1998) The lipophilic behaviour of organic compounds 2. The development of an aliphatic hydrocarbon/water fragmental system via interconnection with octanol-water partitioning data. Quantitative Structure-Activity Relationships, 17, 537-548. 

Common unspecific mode of action of all organic compounds has been taken up in quantitative structure-activity relationships (QSARs see Chapter 5) as the concept of baseline toxicity and in toxicokinetics as the body burden concept (see Chapter 2). Baseline toxicity refers to the idea that a minimum toxicity expectation may be formulated for any given organic compound based on considerations of a compound s partition properties between hydrophilic and lipophilic chemicals (e.g., between water and octanol). Commonly, this is expressed in terms of the octanol-water partition coefficient (K0,J of a chemical. The partition coefficient allows estimations of a local concentration or body burden for each individual chemical in the mixture. Assuming that this produces the same toxic effect (disturbances of cell membranes), it is then possible to anticipate joint narcotic action by adding together the respective local concentrations or body burdens for each individual mixture component. 

Dearden, J.C. (1985). Partitioning and Lipophilicity in Quantitative Structure-Activity Relationships. Environ.Health Persp., 61,203-228. 

Masuda, T., Nakamura, K., Jikihara, T., Kasuya, E, Igarashi, K., Fukui, M., Takagi, T. and Fuji-wara, H. (1996). 3D Quantitative Structure-Activity Relationships for Hydrophobic Interactions. Comparative Molecular Field Analysis (CoMFA) Including Molecular Lipophilicity Potentials as Applied to the Glycine Conjugation of Aromatic as well as Aliphatic Carboxylic Acids. Quant.Struct.-Act.Relat., 15,194-200. 

Classical Quantitative Structure-Activity Relationship Techniques The early QSAR models for calcium channel ligands were based on classical Hansch analysis and elucidated the structural requirements for the binding of molecules to their receptors [111-115], It was found that various steric (Bl, L), electronic (a), and hydrophobic (n) parameters or their combination correlated well with the potency of various DHPs [111]. QSAR analysis of another set of DHPs revealed good correlations between electronic properties (F-constants) of the phenyl ring substituents and binding affinities or functional potency [112] lipophilicity as well as ortho- and meta-substituents inductivity... 

Easily accessible substituents can often be varied to improve the pKa and lipophilic properties of a compound (Chapter 7). Such studies are particularly open to a quantitative approach known as the quantitative structure-activity relationship (QSAR) approach, discussed in Chapter 9. 

The determinants of blood-brain barrier penetration are similar to the determinants of membrane permeability. They include lipophilicity (log P), H-bonding capacity, ionization prohle, size, and flexibility. An example of a simple quantitative structure-activity relationship (QSAR) equation to calculate the ratio of the steady state concentration of the drug molecule in the brain and in the blood have been described" (for a comprehensive review of the in silico methods see" ) ... 

The relationship between chemical structure, lipophilicity, and its disposition in vivo has been extensively studied. These include solubility, absorption potential, membrane permeability, plasma protein binding, volume of distribution, and renal and hepatic clearance. Activities used in quantitative structure-activity relationships (QSAR) include chemical measurements and biological assays. QSAR currently are applied in many disciplines, with many pertaining to drug design and environmental risk assessment. 

Khadikar, P.V., Agrawal, V.K. and Karmarkar, S. (2002) Prediction of lipophilicity of polyacenes using quantitative structure-activity relationships. Bioorg. Med. Chem., 10, 3499-3507. 

Mannhold, R., K. P. Dross, and R. F. Rekker. 1990. Drug lipophilicity in QSAR practice A comparison of experimental with calculated approaches. Quantitative Structure-Activity Relationship 9 21-28. 

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