Classical structure modifications have been the mainstay of drug optimization since the earliest days. As emphasized earlier at several points, structural modifications expressed in organic chemical terms are really only symbols for modification of the physicochem-ical properties of various structures. Nevertheless, the medicinal chemist usually thinks in terms of structure, since that is the language of organic synthesis. It is therefore appro-priate to deal with such an approach, provided one keeps in mind that it is somewhat obsolete because it is twice removed from the arena of drug–receptor interactions.
3.4.1.1 Variation of Substituents via Homologation
The first approach is to vary substituents. The variation of substituents can follow many directions. It can be used to increase or decrease the polarity, alter the pKa, and change the electronic properties of a molecule. Exploration of homologous series is one of the most often used strategies in this regard, because the polarity changes that are induced are very gradual. Homologation is a standard first approach to substituent variation; indeed, a
“standard joke” in medicinal chemistry is to pursue the “methyl, ethyl, propyl, … futile”
series of analogs. Despite the somewhat facetious nature of this statement, there are many examples in which homologation is important to drug design.
The case of the antibacterial action of aliphatic alcohols has been known in detail for many years; an increase in chain length leads to increased activity, with a sudden cutoff point at C6–C8, due to insufficient solubility of these homologs in an aqueous medium because of their high lipophilicity. On the other hand, local anesthetics depend on lipid solubility in the membrane, and the duration of anesthesia produced by the nupercaine derivatives varies between 10 and 600 minutes for a series of alkyl substituents ranging from a simple -H to -n-pentyl. Another well-known example is the profound qualitative change in action between promethazine (3.5), an H1-antihistaminic drug in which two -CH2- groups separate the ring and side-chain nitrogens, and promazine (3.6, an analog of promethazine), which has three methylene groups and predominantly exhibits tran-quilizing properties. Higher homologs can, on occasion, become antagonists of the lower members of a series.
3.4.1.2 Introduction of Double Bonds
The introduction of double bonds changes the stereochemistry of a molecule and decreases the flexibility of carbon chains. The E and Z isomers may show very differ-ent binding properties; for example, the ∆1-double bond of prednisone (3.7) increases its activity against rheumatoid arthritis over that of its parent compound cortisol (3.8)
by about 30-fold. Decreasing molecular flexibility is also important in drug design. If a drug molecule is too flexible, it will be able to fit into too many different receptors, leading to undesirable effects and toxicity.
3.4.1.3 Variations in Ring Structure
Variations in ring structure are endless in drug synthesis, and are often used in the service of some other change or are introduced simply for patent-right purposes. Inspection of
some of the bewildering variations of rings in the older H1antihistamines reveals them to be simply variations on the ethylenediamine structure, differing only quantitatively in their effect. Sometimes, however, relatively minor changes in ring structure lead to profound qualitative changes. The most famous example of this occurs in the transition from the neuroleptic dopamine-blocking phenothiazine drugs to the antidepressant dibenzazepines such as imipramine, in which the replacement of -S- by -CH2-CH2 -changes the molecular geometry.
Ring opening or closure usually leads to subtle changes in activity, provided that nothing else changes. Three examples (among many possibilities) come to mind: incor-poration of the N-methyl substituents of chlorpromazine (1.3) into a closed piperazine ring in prochlorperazine tremendously increases the antiemetic effect while the neu-roleptic activity declines. Of course, this may be due to the introduction of a new basic center. In thioridazine (3.9), the neuroleptic effect increases with the introduction of a closed ring, but extrapyramidal side effects (tremor, stooped posture, slow and shuffling gait) become noticeable.
The inclusion of rings helps to conformationally constrain a molecule and make it less flexible. As discussed in the previous section, this is a desirable design strategy.
Incorporating alkyl rings may change the solubility of the molecule, increasing lipophilic-ity. The incorporation of an aromatic ring may change the pharmacokinetics of the drug.
3.4.1.4 Structure Pruning and Addition of Bulk
As noted earlier, the pharmacophore of a drug is usually confined to a few functional groups or parts of the whole molecule, which can be a large one. In the case of such com-plex natural products as alkaloids, which may be difficult or impractical to synthesize (e.g., tubocurarine (3.10)), the first design attempt is usually directed at simplification of the molecule, pruning away those structural elements that are not part of the phar-macophore and do not serve to hold crucial binding groups in their appropriate posi-tions. The most successful dissection of a molecule can be seen in the case of morphine.
Starting with morphine (3.11), the oxygen bridge (i.e., the furan ring) is first removed, resulting in levorphanol (3.12), a morphinan. By eliminating ring C, the benzomorphan series is obtained. Its most successful member is pentazocine (3.13), which retains only the two methyl groups from ring C and has a lower addiction liability. The simplest (and, incidentally, oldest) modification of the morphine molecule is seen in meperidine (3.14),
a phenylpiperidine that has many congeneric analogs. Fentanyl (3.15) is designed along similar lines and has some tremendously active analogs, such as sufentanil. Even in the methadone (3.16) molecule, the remnants of the piperidine ring are discernible. On the basis of these and other analogs, the opiate pharmacophore consists of:
1. A nonbonding N electron pair
2. A phenyl ring, three carbons removed from the N 3. A quaternary carbon, next to the phenyl ring Basically, the same criteria apply to the enkephalins.
The addition of bulky substituents to a drug molecule often results in the emergence of antagonists, since it permits the utilization of auxiliary binding sites on the receptor. This trend is especially noticeable among the neurotransmitters. For example, the anticholiner-gics,β-adrenergic blocking agents, and some serotonin antagonists show this correlation.
Large substituents often prevent enzymatic attack on a drug, thereby prolonging its useful life. This technique was used to impart resistance to β-lactamase to the semi-synthetic penicillins. The need for the proximity of the phenyl group to the lactam is quite interesting: phenylbenzyl penicillin (8–26) is inactive as an enzyme inhibitor because the phenyl group no longer hinders access of the enzyme to the lactam bond.
3.4.1.5 Physicochemical Alterations
Alteration of the physicochemical characteristics within a drug series is, of course, a result of structural modification; it is just our point of view that changes. It is rather difficult to change only a single parameter with any specific modification, with the potential
exception of lipophilicity, which increases with the addition of “inert” hydrocarbon groups. The degree of lipophilicity — so important in drug action and quantitative SAR (QSAR) investigations — is otherwise subject to change together with the Hammet σ-constant, a descriptor of the electron–donor or electron–acceptor capability of a substituent.
3.4.1.6 Isosteric Variations
The isosteric replacement of atoms or groups in a molecule is widely used in the design of antimetabolites or drugs that alter metabolic processes. Isosteric groups, according to Erlenmeyer’s definition, are isoelectronic in their outermost electron shell. However, since their size and polarity may vary, the term isostere is somewhat misleading.
Isosteres are classified according to their valence (i.e., the number of electrons in the outer shell):
Class I: halogens; OH; SH; NH2; CH3 Class II: O, S, Se, Te; NH; CH2 Class III: N, P, As, CH
Class IV: C, Si, N+, P+, S+, As+
Class V: -CH=CH-, S, O, NH (in rings)
Thus, for instance, the exchange of OH for SH in hypoxanthine gives the antitumor agent 6-mercaptopurine (3.17). Fluorine, the smallest halogen, replaces hydrogen well, giving, for instance, fluorouracil (3.18), which is also an antitumor antimetabolite.
Interchanges of -CH- and nitrogen are common in rings, as seen in the antiviral agent ribavirin (3.19).
The oldest example of the use of “nonclassical” isosteres involves the replacement of the carboxamide in folic acid by sulfonamide, to give the sulfanilamides.
Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addi-tion to the exploitaaddi-tion of auxiliary binding sites on dihydrofolate reductase. This con-cept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the same number of atoms or identical electron structure — is really the classical structure modification approach.
3.4.1.7 Correlating Analog Structure with Bioactivity
The approach involving the design of analogs of an active lead compound has remained unchanged for decades, and the expertise of the synthetic medicinal chemist is as much in demand as ever; however, the intuitive process of selecting structural modifications for synthesis becomes circumspect in this approach, and models based on multiple regression analysis and pattern recognition methods, using very powerful computer techniques, are increasingly being employed as aids. It is obviously much faster and cheaper to calculate the required properties of novel compounds from a large pool of data on their analogs than to synthesize and screen all such new compounds in the clas-sical fashion. Only promising candidates are investigated experimentally. The results gained this way are incorporated into the database, expanding and strengthening the theoretical search. Eventually, sufficient material accumulates to aid in making a confi-dent decision about whether the “best” analog has been prepared or whether the series should be abandoned. Quantitative structure–activity relationship studies represent a systematic approach to this correlation of structure with pharmacological activity.
3.4.2 Quantitative Structure–Activity Relationship (QSAR) Studies