represents an approach used by the medicinal chemist for the rational modification Keywords: Bioisostere, Isostere, Drug design, Replacement, Pseudoatoms. + + Chem. Rev. , 96, − Bioisosterism: A Rational Approach in Drug Design George A. Patani and Edmond J. LaVoie* Department of. Pharmacologyonline 1: () ewsletter Bhatia et al. A Review on Bioisosterism: A Rational Approach for Drug Design and Molecular Modification.

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Skip to main content. Log In Sign Up. A Rational Approach in Drug Design. Patani and Edmond J. Classical Bioisosteres A. Monovalent Atoms or Groups 1. Fluorine vs Hydrogen Replacements 2. Interchange of Hydroxyl and Amino Groups 3. Interchange of Hydroxyl and Thiol Groups 4. InLaw he received his M. Divalent Isosteres under the direction of Professor Edmond J.

He is presently 1. Divalent Replacements Involving Double pursuing graduate studies in pharmaceutics. His current research interests Bonds are focused on drug design and controlled drug delivery. Trivalent Atoms or Groups D. Tetrasubstituted Atoms E.

Ring Equivalents 1. Divalent Ring Equivalents 2. Nonclassical Bioisosteres A. Nonclassical Bioisosteric Replacements of Functional Groups 1. Raational Group Bioisosteres 2. Carbonyl Group Bioisosteres 3. Carboxylate Group Bioisosteres Edmond J. LaVoie received his B. Amide Group Bioisosteres in and his Ph. Thiourea Bioisosteres under the direction of Dr. After postdoctoral study with Dr. Morris Kupchan at the University of Virginia, he joined the 6.

Inhe was appointed IV. His current research interests are in the design and synthesis VI. References of cancer chemotherapeutics and in the elucidation of mechanism s of carcinogenesis. Introduction 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.

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.

He further defined other examples from current literature. The emphasis in relationships in a similar manner.

In this review an at- anesthetics to the slime mold Physarum polyceph- tempt has been made to quantitate, in specific alum. To further explain and rationalize the Table 2. Bioisosteric can be considered identical 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.

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.

Groups of Isosteres as Identified by bution of electrons, and which exhibit similar physi- Langmuir cal properties A second synthesis Figure 1. Nonclassical bioisosteres can be synthase. A rings vs noncyclic structures; and B exchangeable groups.

This approach to classifying bioisosteres will be used to review literature examples of those bioiso- steric replacements that have provided useful infor- mation on the structure-activity relationships as- sociated with various pharmacologically active com- pounds. Monovalent Atoms or Groups Similarities in certain physicochemical properties have enabled investigators to successfully exploit Figure 1. These can be di- vided into the following groups: Fluorine vs Hydrogen Replacements naphthyl isomers Table 4.


This greater receptor binding affinity could again be attributed to the The substitution of hydrogen by fluorine is one of inductive effect of the fluorine atom facilitating a the more commonly employed monovalent isosteric stronger interaction with the receptor.

Due to its electronegativ- ity, fluorine exerts strong field and inductive effects on the adjacent carbon atom. Fluorine substitution, Figure 2. Benzodiazepine Receptor Binding Affinity effect at distal sites. However, fluorine can donate for Naphthyl-Fused Diazepines a lone pair of electrons by resonance.

This is com- compound X IC50 nM a monly referred to as its mesomeric effect. The opposing resonance and field effects can nearly 1a H 1b F cancel.

The pharmacological differences can be at- 2a H tributed to the influence of the electron-withdrawing 2b F 55 effect that the fluorine substitution causes on inter- a In vitro potency of the compound to displace [3H]fluni- action with either a biological receptor or enzyme, trazepam from the benzodiazepine receptor.

The antineoplastic agent 5-fluorouracil 5-FU rep- Another good illustration of this monovalent bioi- resents a classical example of how fluorine substitu- sosteric replacement is observed in a recent series of tion of a normal enzyme substrate can result in a anti-inflammatory corticosteroid analogues 3, Figure derivative which can alter select enzymatic processes. Its close teroids were compared. Their relative anti-inflam- similarity to uracil allows this fluoro derivative to be matory activity was normalized to fluocinolone ace- a successful mimetic.

This biochemically altered tonide, which was assigned a potency of Thus, this bioisosteric replace- acetonide served as a positive control and is assigned a relative ment has the capability of mimicking even the potency index of The similarity as well as the capability of the amino group to hydrogen bond 5 shows that, in the case of the pair of compounds to the enzyme are two important factors that facili- possessing a methylene substituent, the presence tate the binding of aminopterin to the enzyme dihy- of an additional fluorine atom at the 6R position drofolate reductase.

With the pair of corticos- teroids with a methyl substituent Z CH3replacement of hydrogen with fluorine at the 9R position, 3d, also increased anti-inflammatory activ- ity relative to 3c.

Bioisosterism: A Rational Approach in Drug Design.

Thus, the ability of fluorine to replace hydrogen is Figure 5. Interchange of Hydroxyl and Amino Groups ability of the amino group to mimic the hydroxyl group at the receptor bioisosteriam. In this study a series desgn The monovalent interchange of amino and hydroxyl 6,9-disubstituted purines were tested for their ability groups is well known and has been successfully to bind to the benzodiazepine receptor in rat brain employed in the development of various pharmaco- tissue. The relative activity of the 9- 3-aminophenyl – logical agents.

The similar steric size Table 7methyl derivative 9a was compared to the 9- 3- spatial arrangement, and the ability of these func- hydroxyphenyl methyl analogue 9b Figure 6.


Bioisosterism: A Rational Approach in Drug Design.

In tional groups to act as either bioisosteirsm bond acceptors contrast to aminopterin where a dramatic difference or donors is likely responsible for their successful use in binding affinity was observed relative to the approahc bioisosteres. Many of these heteroaromatic compounds are capable of tautomerization. The prototropic tautom- erism of heteroaromatic compounds includes all agents wherein a mobile proton can move from one site to another within the heteroaromatic molecule.

Figure 4 illustrates one of the more common types Figure 6. Benzodiazepine Receptor Binding Activity stituent on the neighboring carbon atom within the of Substituted 6- Dimethylamino benzyl-9H-purines ring.

In this example of bioisosteric replacement, pharmacological activity was retained. It is important to note that retention of biological activity based on in vitro data can be critical in those instances where differences between bioisosteric analogues exist with regard to in vivo parameters which may include absorption, distribution, metabolism, or elimination.

While one Figure 9. Interchange of Hydroxyl and Thiol Groups 15c dS 1.

This replacement is based on the analogues with similar potency. However, substitu- ability of both these functional groups to be hydrogen tion with the thiol resulted in enhanced potency bond acceptors or donors. A classical illustration of Table 7. This could be explained by the fact that this replacement being guanine 10a and 6-thiogua- the size of the substituents, described here as the van nine 10b, Figure 7. Therefore, replacement with the amino group, which has a similar size, resulted in similar potency.

However, replacement with the sterically optimal thiol resulted in an analogue which was an order of magnitude more potent. The use of this replacement in the design of novel Figure 7. Long term use of nonste- a heteroaromatic ring, these functional groups can roidal anti-inflammatory drugs NSAIDs for the exist in different tautomeric forms.

Figure 8 il- treatment of rheumatoid arthritis and other inflam- lustrates the most common example wherein a mobile matory diseases has been associated with side effects proton on a nitrogen atom in the aromatic ring can such as gastrointestinal ulceration, bleeding, and be transferred to the heteroatom attached to the nephrotoxicity.

However, the significance of 16b NH2 2. Replacement of the hydroxyl with an amino group resulted in more potent activity toward 5-LO while the potency toward CO remained the same. Comparison of N-[2- Mercaptomethyl phenylbutanoyl] Amino the electronegativity values of oxygen, nitrogen and Acids sulphur Table 8 suggests that this could be a factor IC50 nM that modulates the degree of inhibition of 5-LO.

The basis for the fluorine-hydrogen eters. This study, for example, did provide insight interchange and the hydroxyl-amino interchange into structural features which were critical to their was discussed previously. The existence of this activity bioisostersm inhibitors of these peptidases.

This effect is principally observed of angiotensin II formation with the diuretic and for chemotherapeutic agents whose mechanism of natriuretic responses.

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