Chemical modification can be used for site specific targeting of drugs. This involves introducing metabolically sensitive moieties into drug molecules to control their metabolism and deactivation after producing therapeutic effects. Two key approaches are soft drugs, which are designed to rapidly metabolize into inactive species, and chemical delivery systems (CDS), which use sequential enzymatic conversions to differentially distribute drugs. Computer-aided drug design can help optimize properties like binding affinity, absorption, and pharmacokinetics to aid in developing targeted drugs.

1. Site Specific Targeting:
Chemical Modification
Presented by
Manali Parab
M.Pharmacy Sem IInd
Pharmaceutics Department
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2. Introduction to chemical modification
 One of the most important goals of pharmaceutical research and development is
targeted drug delivery, defined as optimization of the therapeutic index by localizing the
pharmacological activity of the drug to the site of action
 a specific drug receptor is considered as target, and the objective is to improve fit,
affinity, and binding to this receptor that ultimately will trigger the pharmacological
activity
 Developing new therapeutic agents that have a singular target that is, agents that bind
only to a specific receptor. It was hoped that this way any aberrant toxicity would be
avoided, and only the desired therapeutic gain would be produced. Unfortunately, the
situation is not so simple. Most highly active new therapeutic agents designed to bind to
a specific receptor ultimately had to be discarded when unacceptable toxicity or
unavoidable side effects were encountered in later stages of the development.
 There are a number of reasons for this.
 First, side effects are usually related to the intrinsic receptor affinity responsible for the
desired activity.
 Second, although in most cases the desired response should be localized to some organ
or cell, various receptors are often distributed throughout the whole body.
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3.  Third, for most drugs, metabolism generates multiple metabolites that can have
an enhanced or a different type of biological activity or can be toxic.
 Successful targeting: preferential delivery would lead to reduced drug dosage,
decreased toxicity, and increased treatment efficacy
 With reasonable biological activity at hand, targeting to the site of action
should be superior to molecular manipulations aimed at refining receptor-
substrate interactions. However, successful drug targeting is a complicated
problem because bypass various organs, cells, membranes, enzymes, and
receptors before reaching its designated target.
 Hence future drugs will be designed with a preferred metabolic route (targeting
and metabolism considerations should be included in the drug design process
from the beginning) and targeting in mind, and the actual new chemical entity
will have site specificity and selectivity built into its molecular structure.
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4. Other classification
 Other general classifications are also possible. For example, one can
differentiate among first-, second-, and third-order targeting
 First-order targeting refers to restricted drug distribution to the site of action
(organ or tissue).
 Second order targeting refers to selective drug delivery to specific cells (e.g.,
tumour cells), and
 Third-order targeting refers to directed drug release at predetermined
intracellular sites.
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5. PRINCIPLES OF RETROMETABOLIC
DRUG DESIGN
 Advanced chemical-enzymatic–based drug targeting systems obtained with
strategies that are part of an approach designated now as retrometabolic drug
design.
 Rational drug design can be accomplished only by incorporating metabolic
considerations into the design process from the very beginning.
 Retrometabolic approaches represent a novel, systematic method to accomplish
this goal. By combining structure-activity relationships (SAR) with structure-
metabolism relationships (SMR), they allow the design of safe, localized
compounds.
 The retrometabolic designation has been introduced for these drug design
approaches to emphasize that metabolic pathways are designed backward
compared to the actual metabolic processes, in a manner somewhat similar to
E. J. Corey’s retrosynthetic analysis, in which synthetic pathways are designed
backward compared to actual synthetic laboratory operations
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6. retrometabolic drug design loop
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7. Methods to improve therapeutic index of
drug
Active isosteric–
isoelectronic
analogues of a lead
compound
But they are
deactivated in a
predictable and
controllable way
after achieving their
therapeutic role
soft drug
design
A biologically inert
molecule
Requires several
steps in its
conversion to the
active drug and that
enhances drug
delivery
chemical
delivery
system
design
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8. Isosteric analogues
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9. Although the CDS is inactive by definition, and sequential enzymatic reactions
provide the differential distribution and drug activation, SDs are active therapeutic
agents designed to be rapidly metabolized into inactive species.
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10. Drawbacks of retrometabolic design of
drug
 Owing to the considerable flexibility of retrometabolic drug
design, for certain lead compounds a large number of
possible analogue structures can be designed, and finding
the best drug candidate among them may prove tedious
and difficult.
 Fortunately, computer methods developed to calculate
various molecular properties, such as molecular volume,
surface area, charge distribution, polarizability, aqueous
solubility, and partition coefficient allow more quantitative
design. The capabilities of quantitative design have been
further advanced by developing expert systems that
combine the various structure generating rules and
predictive software to provide an analogy-based ranking
order. 10

11. Undergoes metabolism
•For eg. Cannabis Alcohol
Nicotine
Soft
Drug Do not undergo any
metabolism and hence avoid the
problems caused by reactive
intermediates
Metabolism can be avoided only
by going to pharmacokinetic
extremes: highly water-soluble
drugs (e.g., cromolyn) that
essentially just run through the
body or highly lipophilic
compounds that accumulate in
organelles strongly
Lipophobic drugs, such as
enalaprilat (the active
metabolite of enalapril),
lisinopril, cromolyn, and
bisphophonates (e.g.,
alendronate), are essentially not
metabolized in vivo and can be
regarded as examples of hard
drug
Hard
Drug
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12. •Prodrugs
•Pharmacologically inactive compounds that result from
chemical modification of biological active species
•Chemical change is introduced to improve some deficient
physicochemical property
•Prodrug must undergo chemical or biochemical conversion to
the active form.
•Eg. Phenactin which on activation produces paracetamol
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13. SOFT DRUGS
 Soft drugs are active isosteric–isoelectronic analogues of a lead compound, but they are
deactivated in a predictable and controllable way after achieving their therapeutic role
 Designed to be rapidly metabolized into inactive species and, hence, to simplify the
transformation-distribution-activity profile of the lead.
 In soft drug design, the goal is not to avoid metabolism, but rather to control and direct
it. Inclusion of a metabolically sensitive moiety into the drug molecule makes possible
the design and prediction of the major metabolic pathway and makes it possible to
avoid the formation of undesired toxic, active, or high-energy intermediates.
 Consequently, soft drugs are new therapeutic agents obtained by building in the
molecule, in addition to the activity, the most desired way in which the molecule is to
be deactivated and detoxified subsequent to exerting its biological effects.
 They produce pharmacological activity locally, but their distribution away from the site
results in a prompt metabolic deactivation that prevents any kind of undesired
pharmacological activity or toxicity.
 Accordingly, the design of soft drugs should be based on moieties inactivated by
hydrolytic enzymes
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14. Difference between traditional drugs (D) and soft drugs (SD) for the case of
ocular administration. For a traditional drug, a significant portion of the dose administered
reaches the systemic circulation, whereas for a soft drug, the designed-in metabolism, which
generates an inactive metabolite Mi, rapidly deactivates any fraction that might reach the
systemic circulation; hence, the local effect is accompanied by no or just minimal side effects.
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15. Classification of soft drugs
Soft analogues: close
structural analogues of
known active drugs that
have a specific
metabolically sensitive
moiety built into their
structure to allow a
facile, one step
controllable deactivation
and detoxication after
the desired therapeutic
role has been achieved.
Active metabolite-based
drugs.: metabolic
products of a drug
resulting from oxidative
conversions that retain
significant activity of the
same type as the parent
drug. The corresponding
basic principle is that if
activity an
pharmacokinetic
considerations allow it,
the drug of choice should
be the metabolite at the
highest oxidation state
that still retains activity.
Inactive metabolite-
based soft drugs: active
compounds designed
starting from a known (or
hypothetical) inactive
metabolite of an existing
drug by converting this
metabolite into an
isosteric or isoelectronic
analogues of the original
drug such as to allow a
facile, one-step
controllable metabolic
conversion, after the
desired therapeutic role
has been achieved, back
to the very inactive
metabolite from which
the design started
Activated soft
compounds: a somewhat
separate class derived
from nontoxic chemical
compounds activated by
introduction of a specific
group that provide
pharmacological activity.
During expression of
activity, the inactive
starting molecule is
regenerated.
Pro-soft drugs:inactive
prodrugs (chemical
delivery forms) of a soft
drug of any of the classes
above, including
endogenous soft
molecules. They are
converted enzymatically
into the active soft drug,
which is subsequently
enzymatically
deactivated.
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16.  The inactive metabolite and the soft analogue approaches have been the most
useful and successful strategies for designing safe and selective drugs
 Both of these approaches focus on designing compounds that have a moiety
that is susceptible to metabolic, preferentially hydrolytic, degradation built into
their structure.
 This allows a one-step controllable decomposition into inactive, nontoxic
moieties as soon as possible after the desired role is achieved and avoids other
types of metabolic routes.
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17. Inactivity of drug moiety due to
enzymes
 1)Chemicals and xenobiotics are, therefore, not always metabolized only into
more hydrophilic and less toxic substances but also into highly reactive
chemical species that then can react with various macromolecules and cause
tissue damage or elicit antigen production.
 In addition, oxygenases that mediate most of critical metabolic pathways
exhibit not only interspecies but also interindividual variability and are subject
to inhibition and induction
 In different individuals, half lives of various foreign compounds may vary as
much as 10- to 50-fold.
 2) Diseases can alter organs responsible for metabolism of blood-borne
substances, rapid metabolism can be more reliably carried out by ubiquitous
esterases.
 In critically ill patients, it is better not to rely on metabolism or clearance by
organs such as liver or kidney, because blood flow and enzyme activity in these
organs can be seriously impaired
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18. Chemical Delivery System (CDS)
 Novel and systematic ways of targeting active biological molecules to specific
target sites or organs on the basis of predictable enzymatic activation
 Any drug targeting system that requires a chemical reaction to produce it.
 They should include those systems where there is a covalent link between the
drug and the so-called carrier, and, accordingly, at least one chemical bond
needs to be broken to release the active component.
 Chemical drug delivery systems refer to inactive chemical derivatives of a drug
obtained by one or more chemical modifications so that the newly attached
moieties are monomolecular units (generally comparable in size to the original
molecule) and provide a site-specific or site-enhanced delivery of the drug
through multistep enzymatic and/or chemical transformations
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19. Classification of CDS
• exploit site specific traffic properties by
sequential metabolic conversions that
result in considerably altered transport
properties
Enzymatic
physicochemical-based
(e.g., brain-targeting)
CDSs
• exploit specific enzymes found
primarily, exclusively, or at higher
activity at the site of action
Site-specific enzyme-
activated (e.g., eye-
targeting) CDSs:
• provide enhanced selectivity and
activity through transient, reversible
binding at the receptor
Receptor-based
transient anchor-type
(e.g., lung-targeting)
CDSs:
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20. How Chemical Modification occur?
 Two types of bioremovable moieties are introduced to convert the drug into an
inactive precursor form
 A targetor (T) moiety is responsible for targeting, site-specificity, and lock-in,
whereas modifier functions (F1 . . . Fn) serve as lipophilizers, protect certain
functions, or fine-tune the necessary molecular properties to prevent
premature, unwanted metabolic conversions.
 The CDS is designed to undergo sequential metabolic conversions,
disengaging the modifier functions and finally the targetor, after this moiety
fullfills its site- or organ-targeting role
 Prodrug concept became essentially different by the introduction of multistep
activation and targetor moieties.
 Prodrugs contain one or more F moieties for protected or enhanced overall
delivery, but they do not contain T. Thus, they generally fail to achieve true
drug targeting, which is the major pathway to improve the therapeutic index 20

21. Designing of CDS
 Recognizing specific enzymes found primarily, exclusively, or at
higher activity at the site of action, or exploiting site-specific
transport properties
 The strategically predicted multienzymatic transformations result
in a differential distribution of the drug
 For example, successful deliveries to the brain, to the eye
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22. Brain targeting CDS
 It is most developed class and can be classified as enzymatic
physical-chemical–based CDSs.
 If a lipophilic compound that can enter the brain is converted
there to a hydrophilic molecule, one can assume that it will be
‘‘locked-in’’: it will no longer be able to come out.
 Targeting is assisted because the same conversion taking place in
the rest of the body accelerates peripheral elimination and further
contributes to brain targeting.
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23. Schematic representation of the molecular packaging and sequential
metabolism used for brain targeting of neuropeptides. TRH-CDS (8) is included
to provide a concrete illustration for the targetor (T), spacer (S), peptide (P),
adjuster (A), and lipophilic (L) moieties.
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24.  1,4-dihydrotrigonelline↔trigonelline (coffearine) system, in which the
lipophilic 1,4-dihydro form (T) is converted in vivo to the hydrophilic
quaternary form (T+), proved the most useful.
 This conversion occurs because of the NADH ↔ NAD+ coenzyme system,
because oxidation takes place with direct hydride transfer and without
generating highly active or reactive radical intermediates, it provides a
nontoxic targetor system
 Although the charged T+-D form is locked behind the BBB into the brain, it is
easily eliminated from the body as a result of the acquired positive charge,
which enhances water solubility. After a relatively short time, the delivered
drug D(as the inactive, locked-in T+-D) is present essentially only in the brain,
providing sustained and brain-specific release of the acting drug. In this way
drug get locked inside the brain.
 This can be done for other drugs for eg. Steroids hormones, (e.g., anti-infective
agents, anticancer agents, anticonvulsants, antioxidants, antivirals,
cholinesterase inhibitors, monoamine oxidase (MAO) inhibitors,
neurotransmitters, nonsteroidal anti inflammatory drugs (NSAIDs), steroid
hormones) 24

25. COMPUTER-AIDED DESIGN
 Role: To increase understanding and reduce product failures, time
to market, and lifecycle cost.
 Computer-Aided Drug Design (CADD): Computerized models
exist at every step along the way from binding affinity and drug
absorption through pharmacokinetic and
pharmacokinetic/pharmacodynamic modelling to clinical trial
design
 There have been important successes in both computer-aided
structure- and property-based drug design
 For eg. PopED software
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26.  Computer-aided drug design approaches, just as modeling and simulation
approaches in general, are most useful when they:
 (1) can produce predictions or extrapolations that are in agreement with the
experimental results;
 (2) are reliable enough to enable experiments to be performed in silico, saving
at least some of the time, cost and effort of the in vitro/in vivo experiments;
 (3) facilitate the quantitative understanding of a given system or process;
 (4) enable the better representation or visualization of complex processes;
 (5) permit the generation of data that was not possible before their
implementation;
 (6) can yield nonintuitive insights into the mechanism of the corresponding
system or process; and
 (7) can contribute to the identification of unrecognized or missing components,
processes, or functions in a system.
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27. References
 Prodrugs and Soft Drugs, by Hugo Kubinyi Germany
http://www.kubinyi.de/Leysin2-10-12.pdf
 Drug Targeting Technology, Physical Chemical and Biological Methods, edited
by Hans Schreier, Langley, Washington, Published by Marcel Dekker, Inc,
published in 2010
 RETROMETABOLIC DRUG DESIGN AND TARGETING, by Nicholas
Bodor and Peter Buchwald, published by A JOHN WILEY & SONS, INC.,
PUBLICATION, published in 2012
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