Bioisosterism: a Rational Approach in Drug Design
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+ + Chem. Rev. 1996, 96, 3147−3176 3147 Bioisosterism: A Rational Approach in Drug Design George A. Patani and Edmond J. LaVoie* Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08855-0789 Received May 15, 1996 (Revised Manuscript Received July 25, 1996) Contents I. Introduction 3147 II. Classical Bioisosteres 3149 A. Monovalent Atoms or Groups 3149 1. Fluorine vs Hydrogen Replacements 3149 2. Interchange of Hydroxyl and Amino 3150 Groups 3. Interchange of Hydroxyl and Thiol Groups 3151 4. Fluorine and Hydroxyl, Amino, or Methyl 3152 Groups as Replacements for Hydrogen (Grimm’s Hydride Displacement Law) 5. Monovalent Substitutions Involving 3154 Chloro, Bromo, Thiol, and Hydroxyl Groups (Erlenmeyer’s Broadened Classification of Grimm’s Displacement George Patani graduated with a B.Pharm. in 1992 from the College of Pharmaceutical Sciences, Mangalore University at Manipal, India. In 1996, Law) he received his M.S. in Pharmaceutical Science at Rutgers University B. Divalent Isosteres 3155 under the direction of Professor Edmond J. LaVoie. He is presently 1. Divalent Replacements Involving Double 3155 pursuing graduate studies in pharmaceutics. His current research interests Bonds are focused on drug design and controlled drug delivery. 2. Divalent Replacements Involving Two 3155 Single Bonds C. Trivalent Atoms or Groups 3156 D. Tetrasubstituted Atoms 3157 E. Ring Equivalents 3158 1. Divalent Ring Equivalents 3158 2. Trivalent Ring Equivalents 3159 III. Nonclassical Bioisosteres 3160 A. Cyclic vs Noncyclic Nonclassical Bioisosteric 3160 Replacements B. Nonclassical Bioisosteric Replacements of 3165 Functional Groups 1. Hydroxyl Group Bioisosteres 3165 2. Carbonyl Group Bioisosteres 3166 3. Carboxylate Group Bioisosteres 3168 Edmond J. LaVoie received his B.S. in Chemistry from Fordham University 4. Amide Group Bioisosteres 3170 in 1971 and his Ph.D. in Medicinal Chemistry from S.U.N.Y. at Buffalo 5. Thiourea Bioisosteres 3171 under the direction of Dr. Wayne K. Anderson. After postdoctoral study with Dr. S. Morris Kupchan at the University of Virginia, he joined the 6. Halogen Bioisosteres 3172 American Health Foundation in Valhalla, NY. In 1988, he was appointed IV. Conclusion 3172 Professor of Medicinal Chemistry in the College of Pharmacy at Rutgers V. Acknowledgments 3172 University. His current research interests are in the design and synthesis VI. References 3172 of cancer chemotherapeutics and in the elucidation of mechanism(s) of carcinogenesis. I. Introduction for the rational modification of lead compounds into safer and more clinically effective agents. The con- Years of cumulative research can result in the cept of bioisosterism is often considered to be qualita- development of a clinically useful drug, providing tive and intuitive.1 either a cure for a particular disease or symptomatic The prevalence of the use of bioisosteric replace- relief from a physiological disorder. A lead compound ments in drug design need not be emphasized. This with a desired pharmacological activity may have topic has been reviewed in previous years.2-5 The associated with it undesirable side effects, charac- objective of this review is to provide an overview of teristics that limit its bioavailability, or structural bioisosteres that incorporates sufficient detail to features which adversely influence its metabolism enable the reader to understand the concepts being and excretion from the body. Bioisosterism repre- delineated. While a few popular examples of the sents one approach used by the medicinal chemist successful use of bioisosteres have been included, the S0009-2665(95)00066-5 CCC: $25 00 © 1996 American Chemical Society + + 3148 Chemical Reviews, 1996, Vol. 96, No. 8 Patani and LaVoie present review is focused primarily upon specific arrangement of electrons. He further defined other examples from current literature. The emphasis in relationships in a similar manner. Argon was viewed this review was to outline bioisosteric replacements as an isostere of K+ ion and methane as an isostere + + which have been used to advance drug development. of NH4 ion. He deduced, therefore, that K ions and + No attempt was made to be exhaustive or to illustrate NH4 ions must be similar because argon and meth- all of the specific analogues represented within a ane are very similar in physical properties. The single study. biological similarity of molecules such as CO2 and The ability of a group of bioisosteres to elicit similar N2O was later coincidentally acknowledged as both biological activity has been attributed to common compounds were capable of acting as reversible physicochemical properties. In this review an at- anesthetics to the slime mold Physarum polyceph- tempt has been made to quantitate, in specific alum.8 instances, physicochemical effects such as electro- A further extension to this concept of isosteres negativity, steric size, and lipophilicity and to cor- came about in 1925 with Grimm’s Hydride Displace- relate these values to the observed biological activity. ment Law.9,10 This law states: “Atoms anywhere up Thus, an additional objective of this review was to to four places in the periodic system before an inert demonstrate the opportunities that one has in em- gas change their properties by uniting with one to ploying bioisosteres to gain more specific insight into four hydrogen atoms, in such a manner that the the quantitative structure-activity relationships resulting combinations behave like pseudoatoms, (QSAR) associated with a specific class of drugs. which are similar to elements in the groups one to While in some instances such associations were four places respectively, to their right.” Each vertical detailed by the authors of these literature examples, column as illustrated in Table 2, according to Grimm, others were developed on the basis of evident cor- would represent a group of isosteres. relations. To further explain and rationalize the Table 2. Grimm’s Hydride Displacement Law biological activity observed with nonclassical bioiso- steric groups, the observed biological activity has also C N O F Ne Na CH NH OH FH - been correlated with some substituent constants + CH2 NH2 OH2 FH2 + commonly employed in QSAR studies. These obser- CH3 NH3 OH3 + vations are consistent with the fact that bioisosteric CH4 NH4 replacements often provide the foundation for the development of QSAR in drug design.4,6 Recent Erlenmeyer11 further broadened Grimm’s clas- advances in molecular biology, such as cloning of the sification and redefined isosteres as atoms, ions, and various receptor subtypes, have enabled a clearer molecules in which the peripheral layers of electrons definition of the pharmacophoric sites. Bioisosteric can be considered identical (Table 3). replacements of functional groups based on this Table 3. Isosteres Based on the Number of understanding of the pharmacophore and the phys- Peripheral Electrons icochemical properties of the bioisosteres have en- no. of peripheral electrons hanced the potential for the successful development of new clinical agents. 456 7 8 The bioisosteric rationale for the modification of N+ P S Cl ClH lead compounds is traced back to the observation by P+ As Se Br BrH S+ Sb Te I IH Langmuir in 1919 regarding the similarities of vari- + As PH SH SH2 + ous physicochemical properties of atoms, groups, Sb PH2 PH3 radicals, and molecules.7 Langmuir compared the physical properties of various molecules such as N2 The widespread application of the concept of iso- - - and CO, N2O and CO2, and N3 and NCO and found sterism to modify biological activity has given rise them to be similar. On the basis of these similarities to the term bioisosterism. As initially defined by he identified 21 groups of isosteres. Some of these Friedman,2 bioisosteres were to include all atoms and groups are listed in Table 1. He further deduced from molecules which fit the broadest definition for iso- the octet theory that the number and arrangement steres and have a similar type of biological activity, of electrons in these molecules are the same. Thus, which may even be antagonistic. More recently this isosteres were initially defined as those compounds definition has been broadened by Burger as “Com- or groups of atoms that have the same number and pounds or groups that possess near-equal molecular shapes and volumes, approximately the same distri- Table 1. Groups of Isosteres as Identified by bution of electrons, and which exhibit similar physi- Langmuir cal properties...”.5 The critical component for bio- groups isosteres isosterism is that bioisosteres affect the same phar- 1H-, He, Li+ macological target as agonists or antagonists and, 2O2-,F-, Ne, Na+,Mg2+,Al3+ thereby, have biological properties which are related 3S2-,Cl-, Ar, K+,Ca2+ to each other. 4Cu2-,Zn2+ VV Bioisosteres have been classified as either classical 12 - 8N2, CO, CN or nonclassical. Grimm’s Hydride Displacement + 9CH4,NH4 Law and Erlenmeyer’s definition of isosteres outline - - 10 CO2,N2O, N3 , CNO a series of replacements which have been referred VV to as classical bioisosteres. Classical bioisosteres - 2- 20 MnO4 , CrO4 have been traditionally divided into several distinct 21 SeO 2-, AsO 3- 4 4 categories: (A) monovalent atoms or groups; (B) + + Bioisosterism: A Rational Approach in Drug Design Chemical Reviews, 1996, Vol. 96, No. 8 3149 divalent atoms or groups; (C) trivalent atoms or form of 5-FU, 5-fluoro-2′-deoxyuridylic acid, is ulti- groups; (D) tetrasubstituted atoms; and (E) ring mately responsible for the inhibition of thymidylate equivalents. synthase, an enzyme involved in the conversion of Nonclassical isosteres do not obey the steric and uridylic acid to thymidylic acid and critical for DNA electronic definition of classical isosteres. A second synthesis (Figure 1). The increased reactivity of notable characteristic of nonclassical bioisosteres is 5-fluoro-2′-deoxyuridylic acid relative to 2′-deoxy- that they do not have the same number of atoms as uridylic acid is due to the inductive effect of fluorine the substituent or moiety for which they are used as which results in its covalent binding to thymidylate a replacement.