Hansch, Corwin

The fundamental assumption of SAR and QSAR (Structure-Activity Relationships and Quantitative Structure-Activity Relationships) is that the activity of a compound is related to its structural and/or physicochemical properties. In a classic article Corwin Hansch formulated Eq. (15) as a linear frcc-cncrgy related model for the biological activity (e.g.. toxicity) of a group of congeneric chemicals [37, in which the inverse of C, the concentration effect of the toxicant, is related to a hy-drophobidty term, FI, an electronic term, a (the Hammett substituent constant). Stcric terms can be added to this equation (typically Taft s steric parameter, E,). 

It was not until 1962 that the first quantitative structure-activity relationship was published by Corwin Hansch and co-workers [13], relating to the herbicidal activity of a series of phenoxyacetic acids ... 

The attraction of lipophilicity in medicinal chemistry is mainly due to Corwin Hansch s work and thus it is traditionally related to pharmacodynamic processes. However, following the evolution of the drug discovery process, lipophilicity is today one of the most relevant properties also in absorption, distribuhon, metabolism, excretion and toxicity (ADMET) prediction, and thus in drug profiling (details are given in Chapter 2). 

We have tried to cover some of the important aspects of the determination and use oflog P and log D parameters. Far from being exhaushve, this chapter attempted to offer some considerations and perspective in a field where, after 40 years from its beginning at the hand of Corwin Hansch et al, there does not seem to be much alternative to the balance of forces encoded by the octanol-water system to model lipophilicity. 

A few decades ago the range of chemical descriptors used was very limited. Let us take the example of Corwin Hansch s studies, in which he described the relationship between ecotoxicity and a series of parameters, including log P... 

Teri E. Klein Conrad Huang, Thomas E. Ferrin, Robert Langridge, and Corwin Hansch ... 

In the search for more effective post-emergent herbicides, many laboratories have measured the inhibition of photosystem II in chloroplasts i.e., the Hill reaction. In a continuing investigation of this system, ( ) Corwin Hansch s group at Pomona College, in cooperation with BASF in Germany, analyzed two sets of phenyl substituted ureas 17 1,1-dimethyl-3-phenyl, and 38... 

Structure-Activity Relationships. More interesting, and -scientifically, at least - more significant, is the question of why one nitrosamine should be more or less carcinogenic than another. In a general sense, the answer is obvious differences in reactivity within a series are, almost by definition, the result of differences in structure. This concept is one of the cornerstones of physical organic chemistry and, more recently, has been applied extensively to drug systems in a systematic and quantitative way following the initial and continued successes of Corwin Hansch and his coworkers (18-25). 

Introduced by Corwin Hansch in the early 1960s, Hansch analysis considers both the physicochemical aspects of drug distribution from the point of application to the point of effect and the drug-receptor interaction. In a given group of drugs that have analogous structures and act by the same mechanism, three parameters seem to play a major role ... 

Statistical and computational methods have been used to quantify structure-activi relationships leading to quantitative structure-activity relationships (QSAR). The concqpt of QSAR can be dated back to the work of Crum, Brown and Fraser from 1868 to 1869, and Richardson, also in 1869. Many notable papers were published in the period leading up to the twentieth century by men such as Berthelot and Jungfleisch in 1872, Nemst in 1891, Ov ton in 1897 and Meyer in 1899 (7). Professor Corwin Hansch is now regarded by many as the father of QSAR, because of his work in the development of new and innovative techniques for QSAR. He and his co-woikers produced a paper that was to be known as the birtii of QSAR, and was oititled "Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients" (2). 

The third fundamental component in the QSAR model is the mathematical algorithms. Many methods have been used, and in the last years, there has been an increase of the methods, and hence, quite probably this trend will continue, introducing many other methods [4—6]. Classical QSAR methods, used decades ago, were simple linear relationships. Corwin Hansch has been a pioneer of these methods [2]. An example can be the linear relationship between the fish toxicity and the partition coefficient between octanol and water, called Kow [3]. Kow, and its logarithm, called log P, is still the most popular chemical descriptor used in QSAR models for fish toxicity, and it is the base of software programs used by the US Environmental Protection Agency for fish toxicity [11]. The theoretical assumptions for the use of log P are that (1) octanol mimics the lipophylic component of the fish cell, and (2) the toxic effect is due to the adsorption of the chemical substance into the cell. 

This is a database of more than 200,000 molecules, with their measured biological activity, and QSAR/equations derived internally, (at present there are more than 12,500 QSAR), using QSAR program developed by Dr. Corwin Hansch and his group. 

Corwin Hansch, Peter G. Sammes, John B. Taylor, and Peter D. Kennewell, Comprehensive Medicinal Chemistry. The Rational Design, Mechanistic Study, and Therapeutic Application of Chemical Compounds, Vol. 1 General Principles, Pergamon, Oxford, UK, 1990. 

Corwin Hansch and Albert Leo, Exploring QSAR. Fundamentals and Applications in Chemistry and Biology, American Chemical Society, Washington, DC, 1995. 

Corwin Hansch and Toshio Fujita, Classical and Three-Dimensional QSAR in Agrochemistry. Developed from a symposium sponsored by the Division of Agrochemicals at the 208th National Meeting of the American Chemical Society, Washington, DC, August 21-25, 1994, in ACS Symposium Series 606, American Chemical Society, Washington, DC, 1995. 

I extend my sincere appreciation to Corwin Hansch of Pomona College for his particularly enthusiastic assistance in organizing this symposium. My thanks also goes to W. P. Purcell and T. R. Fukuto for their help and participation in the symposium. 

The author thanks Corwin Hansch for invaluable discussions since our first project on this approach began in 1961. 

The author thanks Corwin Hansch for many suggestive discussions and for making the regression analyses. He is also grateful to Minoru Nakajima for his support of this work. 

Not only due to the R05 approach, but also to numerous previous papers in the QSAR field, pioneered by Corwin Hansch, Clog P has become one of the most relevant computed properties when small molecules are initially evaluated and prioritized. In the words of Lombardo et al.-P... 

This study was partially supported (I.V.T.) by the Go-Bio BMBF grant 0313883 (AZ-31P4556), by the New Mexico Tobacco Settlement Fund (T.I.O.) and by data from Sunset Molecular Discovery EEC. This chapter is dedicated to Corwin Hansch, founder of the QSAR field, on his 90th birthday. 

The seminal work of Corwin Hansch initiated the field of QSAR. Two-dimensional and three-dimensional QSAR methods (2-D QSAR and 3-D QSAR) have been widely applied to problems of biological interest. The latter approach has increased in popularity with the introduction of the comparative molecular field analysis (CoMFA) and commercial availability of similar methods. 

The series editors wish this book a wide distribution. It is up to the reader to find out which of the properties and descriptors might be most suitable for describing the data. However, the early warnings by Corwin Hansch, John Topliss, and others should not be forgotten make your model as simple as possible test and include only a few parameters try to achieve an understanding of your model use a test set to check the external predictivity of your model. Molecular descriptors are powerful tools in QSAR studies - but their abuse may lead nowhere. May this book further contribute to their selective and proper use ... 

The octanol-water partition coefficient, logP, has a long history of applications in environmental and pharmaceutical studies. Already more than 100 years ago the activity of local anesthetics was described by Overton [60] and Meyer [61] in terms of oil-water partition coefficients. The logP was recognized as a standard property for description of the lipophilicity of chemicals due to the works of Corwin Hansch in the 1960s [62],... 

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