Chapter 28. Quantitative Structure Activity Relationships Applied to Drug Design

Section VI Editor:

- Topics in Chemistry and Drug Design

Richard C . Allen, Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey 08876

Chapter

28.

Quantitative Structure Activity Relationships Applied to Drug Design

Michael Cory, Wellcome Research Laboratories, Burroughs Wellcome C o . , Research Triangle Park, N.C., 27709

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Introduction This review covers research published during 1978 to 1981 on the application of quantitative structure-activity relationship (QSAR) studies to drug design, extending the review published three years ago. The topic of computerized pharmacophore mappin?, also p-wviously reviewed in this series, will not be discussed here. QSAR research has continued to increase as evidenced by the publication of monograph^^'^ and other review chapters. The consequences of the Hansch approach have been reviewed,6 as have multivariate statistical7 and topological approaches.8'9 The proceedings of meetings devoted to QSAR1'-14 and a review of interpretation of QSAR relationship^'^ have been published. QSAR studies of drug metabolism and distribution have been reviewed. l6

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Methods - The early work which used the bilinear model for nonlinear structure activity relationships has been extended17 and reviewed.l8 A new double parabolic model has also been presented.19 Methods have been described in which the three dimensional conformation of the molecule is used to generate descriptors. These techniques include conformational energy minimization20 and exhaustive computerized search of conformational space with computation of ligand and receptor geometry.21'22 Computation of the steric difference between the ligand and a hypothetical receptor generated from the most active compound in a series has also been discussed.23 The significance of the shape descriptors resulting from these techniques are usually analyzed by regression analysis techniques. Further work has been done on mathematical methods applicable to series design, including criteria for measurement of the suitability of a proposed series24 and two-dimensional mapping of descriptors.25 Suggestions on mathematical methods for normalization of variables to give more interpretable results have been The usefulness of the "jackknife" confidence interval estimator as applicable to QSAR has been discussed.28 The pattern recognition technique of adaptive least squares has been applied to the discrimination of categorical biological data.29 The SIMCA (Simple Modeling of Chemical Analogy) pattern recognition technique has been re~iewed.~' A simple method for solving the Free-Wilson model has also been presented.31 Some o f the statistical hazards associated with multiple regression analysis were discussed. A

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particular distinction must be made between the variables investigated for possib e correlation and those included in a particular equation.32 Parameters - Partition coefficient, expressed either as log P or as is still the most important parameter considered in developing QSAR relationships. Hansch has published a book describing the method for calculation of log P from substructures of the molecule.33 Rekker has expanded on his system of fragment constant^.^^'^^ The Pomona College Medicinal Chemistry Project has continued to add significant numbers of new experimentally determined log P values to their database.36 Since it is rather tedious to measure log P by the solvent partition method, recent workers have concentrated upon the correlation between partition coefficients and other more accessible physical parameters. 37 Chromatography as a tool for determining parameters useful in QSAR has been reviewed.38 Chromatographic constants such as R derived from TLC reverse phase systems for ionic molecules such as ami?es3’ and aryl-alkyl acids40y41 have been correlated with partition coefficient by a number of investigators. Reverse phase HPLC has been correlated with log P using phenols,42 and with T[ using nonionic pesticide^.^^ Gas chromatography behavior has been correlated with partition coefficients for volatile compounds using oleyl alcohol as the stationary phase.44 A series of correlation equations has related log P in octanol and various buffers with log P determined in octanol and water.45 An excellent correlation was obtained between log P in an octanol-N,N-dimethyloctylamine containing buffer system and HPLC R for a series of lipophilic phenothiazines .46 Lo P has also been cor7elated with aqueous solubility,47 connectivity,4’ passive intestinal absorption rates,49 and kinetic transport rates.50 The connectivity parameter x has been correlated with GLC retention times.51’52

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Applications of QSAR Techniques - QSAR techniques have been widely used to study inhibitors of dihydrofolate reductase (DHFR). Molecular properties, obtained from CND0/2 molecular orbital calculations have been used to correlate the inhibition of DHFR by substituted quinazolines.53 Regression analysis was applied to a series of quinazolines as inhibitors of DHFR from human and mouse leukemia cells.54 Hopfinger has correlated the DHFR inhibition activity of a series of 2,4-diaminotriazines (1) with three descriptors of molecular shape and A . The shape descriptors were determined by use of the CAMSEQ-I1 software system.55 Molecular shape analysis studies have also correlated the DHFR inhibition activity of quinazolines (2) and 5-benzyl-2,4-diaminopyrimidines (2). 56’ 57 Recent efforts by Hansch and coworkers have begun to approach the difficult problem of rational design o f mammalian vs. bacterial species specific enzyme inhibitors. Series of compounds were prepared which have less correlation between molecular descriptors and span a wider range of substituents. Physical chemical parameters responsible for the differences in inhibition between the DHFR enzymes for bovine liver and E_. G. were Using substituted 5-ben~y1-2~4-diamino-

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(z),

pyrimidines the equations clearly show the differences in space of the active site of the enzyme, since good correlations were obtained with different physical chemical parameters.58’59 Phenyl 4,6-diaminos-triazine (1)inhibitors of mammalian DHFR enzymes give bilinear correlations with n o f the substitution in the 4-position of the phenyl group.6 o Studies on chymotrypsin have continued with investigation focused on the binding of L-alanine analogs and their effect on the p3 area of the chymotrypsin active site.61 Work has been done on the binding of alkyl phosphonates to chymotrypsin.6 2 Other proteases have been studied with correlations investigating bovine tryptic pro tease^^^ and human serine proteases.64 These studies point up differences in the binding site regions and illuminate the diffiLulty of designing specific inhibitors for related enzymes. The antifibrinolytic activity of a series of arylacetic acids was correlated with lipophilicity. Estimation of lipophilicity by reversed phase thin layer chromatographic correlated poorly with antifibrinolytic activity, but tabulated n values correlated well.65 Lipophilicity of a series of quinoline-3-carboxylic acids (?), as expressed by the HPLC retention index, was the superior parameter correlating with inhibition mitochondria1 but not cytoplasmic dehydrogenase enzymes.66 For example inhibition studies of cholinesterase by a large series of carbamates suggest that the most important parameter for binding is molar refract i ~ n .Studies ~ ~ of rifamycins as inhibitors of various mammalian and viral DNA polymerases indicate that the partition coefficient correlates best with inhibitory potency. Studies using pattern recognition techniques in the antibacterial area have been designed to make comparisons of biological test systems on a quantitative basis. Coates has studied pyrimidines which are reversible or irreversible folic acid antagonists.69 The antibacterial properties o f a series of antibiotics have been classified by cluster analysis.7 0 Darvas used a principal component methodology to investigate

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the mechanism of action of a series of antibacterial y-pyridone-p-carboxylic acids ( 5 ) . Two principal components account for more than 80% of the bacteriostatic activity.7 1 Parabolic relationships have been developed for partition coefficient and antibacterial activity of substituted rifamycin analogs72 and biguanides.73 Applications of QSAR techniques in the area of cancer chemotherapy have been reviewed.7 4 DNA-dependent inhibition of DNA polymerase, DNA binding, mammalian toxicity and tumor selectivity of a series of bisguanylhydrazones was described.7 5 The mammalian toxicity of these compounds was effectively correlated with chromatographically determined Rm values. In a series of studies concerned with DNA binding, mutagenic-

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ity, toxicity, and antitunlor efficacy of a series of 9-anilinoacridines related to the clinical antitumor agent 4‘-(9-acridinylamino)methanesulfonanilide (m-AMSA) ( 6 ) , chromatpgraphically determined R values were used to model partition coefficients. In a large serpes of m-AMSA analogs, the (molar dose required to NHS02CH3 give 40% extension of life in treated animals over untreated controls) correlated with pK and Rm.7*6’77 Mutagenicity correlated with partition coefficient as the dominant factor. Correlation equations CH3O suggested that mutagenicity and antitumor activity can be separated by appropriate choice of substituents and adjustment of the partition coefficient.78 Studies of a series of anthracyclines suggest that most structural modifications which lead to an increased partition coefficient, increase 6 both antitumor activity and cardiac t~xicity.~’ Studies of of a series of nitroaromatic compounds show that one electron reduction potential and lipophilicity correlate with the radiosensitizing activity.80 Partition coefficient proved to be the most important parameter for correlating the antitumor activity of a series of substituted phenyl-3,3-dimethyltriazines.81 In another study, equations correlating toxicity were similar to those correlating antitumor activityYa2 suggesting that the therapeutic ratio cannot be improved in this series. In a similar study of a series of nitrosoureas, comparison of the correlation equations of the partition coefficient and an indicator variable suggests that toxicity and antitumor activity can be separated by proper adjustment of lip~philicity.~~ The antileukemic activity of a series of colchicine analogs against P388 cells was correlated with partition ~ o e f f i c i e n t . ~The ~ activity of a series of nitrosamine carcinogens has been correlated with water-hexane partition coefficient and electronic factors represented by a.85 The mutagenicity of a similar set of compounds tested in the Ames bacterial mutagenicity assay has been correlated with molecular connectivity.86 The mutagenicity of a large series of polycyclic heterocyles evaluated in the Ames test correlated with partition coefficient and the minimal topological difference parameter defined by Simon.87y88 Finally, the mutagenicity of a series of substituted o-phenylenediamineplatinum dichlorides has been correlated with a-.89

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Pattern recognition techniques using descriptors based upon substructure, connectivity, and geometry have been used to correlate a heterogeneous set of carcinogens,90 and a large series of carcinogenic aromatic amines .” Parameters investigated in these two studies include substructure, molecular connectivity, and geometric descriptors, such as the principal moments of inertia and the molecular volume. The carcinogenic activity of a set of polycyclic aromatic hydrocarbons was classified using the SIMCA pattern recognition technique. Twenty three parameters, including theoretical parameters derived from quantum mechanical computations and measured parameters, such as ionization potential, were used. 92 The partition coefficient between buffer and erythrocytes for a series of antimalarial bis-arylsulfonamides was correlated with lipophilicity, as described by Rd and the PK,.’~ A series of 646 arylcarbinols with a 1000-fold range of activity against p. berghei in mice was corre-

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lated. The equation covering all compounds contained a series of indicator variables to account for the different relative contributions of the aromatic ring systems, and the partition coefficient and 0 o f the ring substituents as significant parameters.9 4 QSAR prediction of high muscarinic receptor antagonist activity for

a series of quaternary diethylaminoethyl-xanthenylmandelates ( L ) was not

confirmed.” The muscarinic receptor binding activity of a series of aryl substituted alkyltrimethylammonium quaternary agents ( S ) has been

correlated with n for the aromatic side chain and a bulk parameter for side chain substituents. An indicator variable accounts for differences in the fit of the aromatic ring on the receptor site.96 A study of a series of 100 muscarinic antagonists and agonists using molecular connectivity parameters showed that the quaternary ammonium group contributes equally to agonist and antagonist activity, while the structure of the side chain strongly influences antagonist activity.97 Correlations between molar volume and inhibition potency against mouse-brain synaptosomal lysophosphatidylcholine acyltransferase has been observed i n a series of psychoactive cannabinoids. Use of a molar volume parameter allowed separation of nonspecific lipophilicity effects Chromafrom intrinsic binding affinity to the membrane bound enzyme.98 tographic R values from a reverse phase system correlated well with m measured or experimental log P values for a series of benzodiazepines.” The CNS activity of these compounds as measured by exploratory and conflict behavioral tests, correlated with R values and structural indicator variables. Different slopes for the term in the correlation m equation suggest a different dependence upon partition coefficient, and a different mechanism of action for exploratory and conflict behavior.”

In a study of a series of aminoxylidines ( 9 ) , anti-arrhythmic activity and acute CNS toxicity, characterized by ataxia, were correlated with measured partition coefficient and pK . Correlation equations suggest a that increases in the pKa of this class of compounds would increase the therapeutic index. Anti-arrhythmic activity correlated with partition coefficient alone.l o o Pattern recognition techniques identified connec-

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tivity fragments and substructure descriptors as the significant structural parameters which correlate with duration of action of a large series of barbiturates. l o l The anticonvulsant and CNS-depressant activity, and toxicity of a series of antiepileptic drugs, as measured, respectively, by the maximal electroshock and pentylenetetrazol seizure tests, and median toxic dose, was correlated with log P and dipole moment values. lo2 The duration of action of a series of phenylsuccinimide anticonvulsants, active against maximal electroshock seizures, was correlated with the hydrophilicity of the substituent on the nitrogen. l o 3 Similarly, the anticonvulsant activity of a series of 4-arylpiperazines

A

R3-A

-NwNR2

R1

11 -

0

(lo) correlated with computed log P. Increased lipophilicity directly correlated with increased potency. l o 4 Protection against maximal electroshock seizure's by a series of substituted aromatic sulfonamides (11) was correlated with Swain and Lupton's F constant and 71. Steric parameters for substituents on the ring, and substituents on the nitrogen improved the correlations.lo5 The cardiotoxicity of a series of steroidal aglycones was mapped by use of the minimal steric difference correlation method. lo6 The optimized superposition of the molecule provides a map of the site of the cardiotoxic receptor, which has a high degree of predictability. l o 6 Pattern recognition techniques were used to classify a series of steroids into five therapeutic categories. A template for each class and first-order molecular connectivity parameters on

?CH2CHCH2NHR1 I

13 -

NHCONHR

--12 were useful for classification.lo' Free-Wilson analysis of a large series of ureido phenoxy-3-amino-2-propanol (12) f3-adrenergic blocking agents suggested that regression analysis would require inclusion of indicator variables for specific substitution patterns.log A significant relationship was developed between sigma and and the indicator variables. l o g

n,

The local anesthetic activity of a series of N,N-disubstituted aminoacetylarylamines (13) correlated best with molar refraction giving a parabolic relationship significantly superior to equations with partition coefficient. Intravenous toxicity based on LD5o data correlated with partition coefficient in a parabolic relationship.l o g A multiple regression model using substructural parameters based upon the Edgewood Arsenal fragment code should be useful in ranking of potentially toxic

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compounds. lo The pharmacokinetic parameters, elimination rate constant, clearance, and protein binding of a series of 2-sulfapyridines have been correlated with physicochemical parameters such as chromatographically deri.ved partition coefficients, pK , and steric parameters. Protein binding increases with lipophilicity and pKa. The steric effect of substituents on the binding of the compounds to bacterial enzymes is opposite that of binding to serum proteins. Pharmacokinetic data from studies of the metabolism of N-substituted amphetamines in humans has been correlated with lipophilicity and structural parameters describing the nitrogen substitution patterns. Partition coefficients measured in n-heptane-pH 7.4 buffer gave a better correlation with urinary The excretion than calculated octanol-water partition coefficients.'12 binding of a series of barbiturates to cytochrome P-450 and their hepatic clearance have been correlated in a parabolic relationship with calculated log P and the volume of the 5-substituent. The regression equations for P-450 binding were similar to those for hepatic clearance. l 3 The activity of a series of p y r i d i n e c a r b o n y l d i t h i o c a r b a z a t e s , which uncouple oxidative phosphorylation,was correlated with lipophilicity and indicator variables.'l* The sweetness of a series of aspartyl dipeptide methyl esters was correlated with n. '15

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