1

Site Specific Targeting: Chemical Modification

Presented by Manali Parab

M.Pharmacy Sem IInd

Pharmaceutics Department

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.

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.

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.

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

6

retrometabolic drug design loop

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

8

Isosteric analogues

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.

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.

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

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

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

14

Difference between traditional drugs (D) and soft drugs (SD) for the case ofocular 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.

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.

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.

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

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

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:

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

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

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.

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.

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)

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

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.

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