SELECTION OR SYNTHESIS OF HARD & SOFT DRUGS

Presented By:- Mr. Dinkar B. Kamkhede

MSc.Chemistry,IIYear

2014 .

Vidyabharati Mahavidyalaya

Amravati.

Sat.22,March 2014

Contents-

1) Selection of Hard & Soft Drug

Types, Feature, Advantage, Difference

2) Clasification of Soft Drug

Soft Anologs , Activated, Natural Soft Drugs

Active, Inactive Metabolite Approach.

3)Prodrug Metabolisam

Bioprecausor, Carrier Prodrug,Prodrug System.

Intoduction

The drug is most commonly an organic small molecule that activates or

inhibits the function of a biomolecule such as a protein, which in terrn

results in a therapeutic benefit to the patient.

Drug is single active chemical moity which is found in medicine & used

for dignosis , prvention, treatment &cure of a diseases .OR

According to WHO Drug is any substance or product i.e used or intended

to be used to modify or explore physiological system or pathological state

for the benefits of recipients.

Drugs are divided into two types based on their

Metabolic susceptibility.

1)Hard drugs: these can be defined as drugs that are

biologically active and non metabolizable in vivo

Ex: enalaprilat, lisinopril, cromolyn, and bisphophonates

2)Soft drugs: these can be defined as drugs that

Are produce predictable and controllable in vivo metabolism to form

nontoxic product after they have shown their therapeutic role.

Ex: cetyl pyridinium chlorides, soft cloramine

SELECTION OF HARD AND SOFT DRUGS

Ex. Hard drugs are those that are resistant to metabolism, hence avoid problems ,

caused by reactive intermediates and some times these are

remain unchanged in the body,

These are characterized by high lipid solubility ,

accumulation in adipose tissue and organelles are high water solubility

A few successful examples of hard drugs include bisphophonates ,ACE inhibitors.

Ex :cromoglicic acid

Hard drugs

1) High lipid-soluble drugs:

In this compounds the metabolically sensitive parts are blocked by “stearic packing” (or) by substitution of hydrogen atom with halogen . Ex: hard celecoxib.

2) High water -soluble drugs:

These drugs lack substrate properties to the

metabolizing enzymes,

Their biological half life is very short and

these are very potent compounds .

Ex:cromoglicic acid.

Hard drugs are divided into two types;

Soft drugs are biologically active drugs designed to have a predictable and

controllable metabolism to nontoxic and inactive products after they have

achieved their desired pharmacological effect.

The molecule could be deactivated and detoxified shortly after it has exerted its

biological effect, the therapeutic index could be increased, providing a safer

drug.

Feature

It has a close structural similarity to the lead;

It has a metabolically sensitive moiety built into the lead structure;

The incorporated metabolically sensitive spot does not affect the overall

physicochemical or steric properties of the lead compound.

Soft Drug

Elimination of toxic metabolites, thereby increasing the therapeutic index of the

drug;

Avoidance of pharmacologically active metabolites that can lead to long-term

effects;

Elimination of drug interactions resulting from metabolite inhibition of enzymes;

Simplification of pharmacokinetic problems caused by multiple active species.

Advantages

The concepts of prodrugs and soft drugs are opposite, as follow:

A prodrugs is an inactive compound that requires a

metabolic conversion to the active form;

A soft drug is pharmacologically active and uses metabolism

as a means of promoting excretion

However, it is possible to design a pro-soft drug, a modified soft drug that

requires metabolic activation for conversion to the active soft drug.

It is not possible to prepare soft-pro drug

The difference between prodrugs and soft durgs

Sat.22,March 2014

Soft drugs are divided by Bodor into five different groups.

Classification of soft drugs:

1. Soft analogs

2. Activated soft compounds

3. Natural soft Drugs

4. Soft Drugs based on active metabolite approach

5. Soft Drugs based on inactive metabolite approach

Sat.22,March 2014

The simplest example of the soft analog is the isosteric analog (II) of

cetylpyridinium chloride (I) which is a hard quaternary antimicrobial agent.

Soft analogs are close structural analogs of

known active drugs or bio active compounds

These compounds have a specific “metabolically sensitive spot built into their structure which provide their one-step controllable detoxification .

These sensitive spots are not oxidizable alkyl chains or

functional groups subjected to conjugation .

The designed detoxification will take place as soon

as possible after the desired activity is achieved .

Soft analogs

These compounds are not the analogs of known drugs

These are designed by introducing a pharmacophoric group in a

nontoxic inactive compound in order to activate it to exhibit a certain

pharmacological activity.

In vivo the activated form will lose the activating group and revert to

the original nontoxic compound1

Ex: soft chloramine are less corrosive(where the chlorine atom

attached to hetero atom) than the conventional chloramines .

Ex: chloramine-T is available in salt form so it is less corrosive.

Activated soft compounds:

Ex: the use of di esters of adrenalone to deliver the epinephrine the eye

via combined reduction and hydrolysis process .

The endogenous substances can be considerd as natural soft drugs since the body

possesses efficient, fast metabolic pathways for their deposition without going through

highly reactive intermediates .

Ex: neurotransmitters, steroidal hormones .

Natural soft drugs:

Ex: Oxyphenbutazone the active p-hydroxy metabolite of phenylbutazone

Oxazepam the common active metabolite of chlordiazepoxide, halazepam,

chlorazepate and diazepam

Some drugs under go step wise biotransformation giving intermediates and

structural analogs with which have activity similar to that of the original molecules

According to Bodor it is preferable to use as the drug of choice an active

species which under goes a one step ,singular, predictable metabolic deactivation.

Soft Drugs Based on Active Metabolite Approach

Ex: Chlofenotane, the acidic metabolite “v” which is inactive of relatively

low toxicity excreted as water soluble species, it is lead compound for the

inactive metabolite approach.

That is the ethylester of clofenotane.

Soft Drugs Based on Inactive Metabolite Approach

This is done by three steps-

a) Activation stage: chemical modification of a known “inactive metabolite of a drug (by iso sterism ), this metabolite used as a lead compound.

b) Predictable metabolism: design of structure of new soft analog in such a

way that its metabolism will yield the starting inactive metabolite in one step

without going through toxic intermediate.

c) Controllable metabolism: control of transport and binding properties as

well as rate of metabolism and pharmacokinetics by molecular modification.

Prodrug Metabolism

Prodrugs can be broadly classified into two groups:

Bioprecursors

Carriers

They may also be sub-classified according to the nature of their action

(Ex. photoactivated .

Inactive compounds that yield an active compound in the body

Conversion is frequently carried out by enzyme-controlled

metabolic reactions and less frequently by chemical reactions within the body.

Prodrugs are used as a way to:

Increase lipid or water solubility,

Improve that taste of a drug to make it more patient compatible,

Alleviate pain when the drug is administered parenteally by injection,

Reduce toxicity , Increase chemical stability, Increase biological stability,

Change the length of the time of duration of action,

Deliver the drug to a specific site in the body.

Bioprecursor Prodrugs

Carrier Prodrugs

Prodrugs System

The choice of the functional group used as a metabolic link depends

both on the functional groups occurring in the drug molecule and the

need for the prodrug to be metabolized in the appropriate body

compartment.

Using prodrugs to improve absorption and transport through membranes.

REFERENCES-

R.L.Juliano

E.B.Roche

N.Bodar.

S.N.Pandeya

Sat.22,March 2014

Sat.22,March 2014