Ynthesis and Structure-Activity Relationships of Some 4-Substituted Pyrazole and Isoxazole Inhibitors of Liveralcohol Dehydrogenase

AN ABSTRACT OF THE THESIS OF Douglas Robert Henry for the degree of Doctor of Philosophy in Pharmacy presented on July 10, 1980 Title: I. SYNTHESIS AND STRUCTURE- ACTIVITY RELATIONSHIPS OF SOME 4-SUBSTITUTED PYRAZOLE AND ISOXAZOLE INHIBITORS OF LIVER ALCOHOL DEHYDROGENASE II. THE USE OF MOLECULAR CONNECTIVITY IN THE MULTIVARIATE CLASSIFICATION OF DRUG MOLECULES Redacted for Privacy Abstract Approved: U Dr. John H. Block In a two part thesis, studies were made of two different types of structure-activity relationships. The first part consists of the synthesis and biological evaluation of a number of 4-substituted pyrazoles and isoxazoles as inhibitors of liver alcohol dehydrogenase. In an effort to better define the steric and electronic effects of substituents, the inhibitory potencies ofthe compounds were determined in vitro, and these were correlated with the lipophilicity parameter IFand with several steric and electronic substituent constants. Lipophilicity showed the most significant relationship with activity. Electronic terms were less significant, but a consistently negative slope coefficient for these terms suggests that a positive charge develops on the pyrazole ring during interaction with LADH, which is not consistent with a previously proposed anionic intermediate. In the second part of the thesis, retrospective research was performed to determine the usefulness of fragment and whole-molecule molecular connectivity (MC) indices in the multivariate classification of drug structures. Initially, using a template method of position assignment, a number of diphenylmethyl-based compounds from a previous study were examined using linear and quadratic discriminant analysis. Relative molar refraction was compared with several fragment MC values as descriptor indices. First order fragment MC was found to be the most usefuldescriptor of those examined, and this was verified in a second study using a number of steroids classified into five therapeutic categories. In a third study, these steroids were examined using a number of pattern recognitiontechniques. It was concluded that there was no advantage tothe use of pattern recognition techniques over discriminant analysis, especially since stepwise variable selectionis available in the latter. Finally, using a composite of the structures that had been studied, a comparison was made between the recently introduced SIMCA method of modelling and classification, and conventional discriminant analysis. Simple and valence whole-molecule MC indices were used as descriptors to avoid the problems of position assignment. The original sample classification results were similar using both techniques. When a holdout-by-four method of validation was performed, linear discriminant analysis gave better results than either SIMCA or the quadratic discriminant function. This reflects the effects of small sample sizes on the latter two methods.A comparison of the canonical discriminant function values and the principal component scores from SIMCA as predictors of the quantitative potencies of a number of androgens was made, and higher correlations were found with the discriminant function values. This evidence again suggests that no advantages are gained by using techniques other than discriminant analysis, although more experience with pattern recognition methods is necessary to becertain of this conclusion. I. Synthesis and Structure-Activity Relationships of Some 4-Substituted Pyrazole and Isoxazole Inhibitors of LiverAlcohol Dehydrogenase II. The Use of Molecular Connectivity in the Multivariate Classification of Drug Molecules by Douglas Robert Henry A THESIS Submitted to Oregon State University in partial fulfillment of the requirements for the degree of Doctor ofPhilosophy Completed July 1980 Commencement June 1981 APPROVED: Redacted for Privacy Prof sor of Pharmaceutical Chemistry in charge of major Redacted for Privacy Dean of Pharmacy School Redacted for Privacy Dean f Graduate School d\ Date thesis is presented July 10, 1980 Typed by Douglas R. Henry ACKNOWLEDGMENTS I am grateful for: The love and patience of my parents and my brother, who never once (well, almost never) asked how much longer. The tolerance and enthusiasm of my adviser Dr. Block. We swam together through an ocean of multivariate statistics, at times keeping each other afloat. His patience and understanding was more than I ever deserved, and I shall always be proud to count him as my adviser and friend. The wisdom and humor of Dr. Doerge, who must look with a certain amusement at a breed of medicinal chemists who would rather do their chemistry on a computer terminal than in a flask. The help and cooperation of Dean Ohvall and all the faculty and staff of the School of Pharmacy.They are part of the reason I never really wanted to finish and leave. And finally, the acquaintance with so many fellow students, both undergraduate and graduate, who have taught me that friendship is the most precious gift of all. If I had to choose between a single one of my friends and all the honor and reward that any degree could ever bring, the choice would be a simple one. I feel blessed that I could have the best of both. TABLE OF CONTENTS Page Part I. SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF SOME 4-SUBSTITUTED PYRAZOLE AND ISOXAZOLE INHIBITORS OF LIVER ALCOHOL DEHYDROGENASE 1 Chapter One SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF SOME 4-SUBSTITUTED PYRAZOLE AND ISOXAZOLE INHIBITORS OF LIVER ALCOHOL DEHYDROGENASE 2 Abstract 3 Introduction 4 Results and Discussion 19 experimental 32 Acknowledgment 41 References 42 Part II. THE USE OF MOLECULAR CONNECTIVITY IN THE MULTIVARIATE CLASSIFICATION OF DRUG MOLECULES 47 Chapter Two CLASSIFICATION OF DRUGS BY DISCRIMINANT ANALYSIS USING FRAGMENT MOLECULAR CONNECTIVITY VALUES 48 Abstract 48 Experimental 49 Results and Discussion 51 Acknowledgment 55 References 55 TABLE OF CONTENTS (CONTINUED) Page Chapter Three STEROID CLASSIFICATION BY DISCRIMINANT ANALYSIS USING FRAGMENT MOLECULAR CONNECTIVITY 56 Abstract 57 Introduction 58 Experimental 59 Conclusions 76 Acknowledgment 81 References 82 Chapter Four PATTERN RECOGNITION OF STEROIDS USING FRAGMENT MOLECULAR CONNECTIVITY 84 Abstract 85 Introduction 86 Experimental 87 Results and Discussion 95 Conclusions 108 Acknowledgment 110 References 111 Chapter Five MULTIVARIATE CLASSIFICATION OF DRUGS USING MOLECULAR CONNECTIVITY DESCRIPTORS 114 Abstract 115 Introduction 117 Experimental 123 Results and Discussion 124 Summary and Conclusions 151 Acknowledgment 154 References 155 TABLE OF CONTENTS (CONTINUED) Page Appendix One CALCULATION OF FRAGMENT MOLECULAR CONNECTIVITY VALUES 158 Appendix Two PROGRAMS FOR REGRESSION ANALYSIS AND KINETIC CALCULATIONS 162 Appendix Three PLOTTING PROGRAMS 176 LIST OF FIGURES Figure Page Chapter I 1 Pyrazoles in the active site of LADH 10 2 Observed versus predicted potencies of pyrazoles and isoxazoles 29 +2 3 Possible mechanisms for the Zn-NAD-pyrazole interaction 31 Chapter II 1 Structures of additional design set compounds 50 2 Structures of compounds in the test set 52 3 K-Nearest neighbor classification results 53 4 Plot of the design set compounds in the space of the first three canonical discriminant functions 53 Chapter III 1 Plot of the learning set compounds in the space of the first three canonical discriminant functions of the MC index 74 1 2 Structures of the compounds in the test set 77 Chapter IV 92 1 Structures of the compounds in the test set 2 Andrews' function plots of the group centroids of each of the therapeutic categories 97 3 Plot of the total sum-of-squares ofdifferences between each of the possible pairsof curves shown in Figure 1. 98 4 Histogram of the Andrews' functionvalues for the compounds in this study 100 LIST OF FIGURES (CONTINUED) Figure Page Chapter V 1 Stereo plot of the nonsteroid compoundsin the space of the first threecanonical discriminant functions 130 2 Stereo plot of the steroids in the spaceof the first three canonical discriminant functions 131 3 Subcutaneous potencies of androgens onventral prostate and seminal vesicleindices as a function of the fifth canonical discriminant function 150 Appendix I 1 Calculation of fragment molecular connectivity indices used in this research 161 LIST OF TABLES Table Page Chapter I I Pyrazole Inhibitors of LADH 8 II Correlation Matrix for Table I 9 III Pyrazoles and Isoxazoles Used in this Study 14 IV Substituent Constants and Potencies for Compounds in Table IV 20 V Correlation Matrix for Tables I and IV 22 Chapter II I Raw MCValues for the Compounds Used in the 1 Analyses 49 II Correlation Matrix Showing Pairwise Comparisons of the Descriptor Indices 50 III Positions Which Showed Constant Values (i.e., Zero Variance) Within a given Group 51 IV F Values for the Decrease in Significance from the Full Eight-Variable Model 51 V Variable Selection Table Showing the Five "Best" Five-Variable Models with the Associated F Values 51 VI Linear Test Space Classification Results 52 VII Derivation of the Canonical Discriminant Functions Which MaximizeW-1B for the MC Index 53 1 VIII Reduced Space Classification Results Using the Three Most Significant Discriminant Functions 54 IX Quadratic Reduced Space Classification Results for Test Compounds 54 LIST OF TABLES (CONTINUED) Table Page Chapter III Raw MC Values of the Compounds Used in the Analys6s 61 Correlation Matrix of Pairwise Comparisons Between the Various Indices 67 Variable Selection Table Showing the Decrease in Significance from the Full Ten-Variable Model 68 Summary of the Classification

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