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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.
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.