SELECTION OR SYNTHESIS OF SELECTION OR SYNTHESIS OF HARD AND SOFT DRUGSHARD AND SOFT DRUGS

Presented by,

J.NARESH.

SELECTION OR SYNTHESIS OF HARD SELECTION OR SYNTHESIS OF HARD AND SOFT DRUGSAND SOFT DRUGS

•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 eg: 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.• eg: cetyl pyridinium chlorides, soft cloramine

• Hard drugs:Hard drugs:• 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 bisphosphonates and ACE inhibitors.

• Hard drugs are divided into two types;

• 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

• Eg: 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

• eg:cromoglicic acid

Soft Drug• 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

Advantages

• 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.

The difference between prodrugs and soft durgs

• 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

• Classification of soft drugs:Classification of soft drugs:• Soft drugs are divided by Bodor into five different

groups

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

• Soft analogs:• 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

• The simplest example of the soft analog is the isosteric analog (II) of cetylpyridinium chloride (I) which is a hard quaternary antimicrobial agent

• Activated soft compounds:Activated soft compounds:• 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 compound

Eg: soft chloramine are less corrosive(where the chlorine atom attached to hetero atom) than the conventional chloramines

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

• Natural soft drugs:Natural soft drugs:• 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

Eg: the use of di esters of adrenalone to deliver the epinephrine the eye via combined reduction and hydrolysis process .

• Soft Drugs based on active metabolite Soft Drugs based on active metabolite approach:approach:

• 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.

• Eg: Oxyphenbutazone the active p-hydroxy metabolite of phenylbutazone

• Oxazepam the common active metabolite of chlordiazepoxide, halazepam, chlorazepate and diazepam

• Soft Drugs based on inactive metabolite Soft Drugs based on inactive metabolite approach: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.

• Eg: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

References: Andrejus Korolkovas ESSENTIALS OF MEDICINAL CHEMISTRY, 2ND EDFriary, R. Jobs in the Drug Industry A Career Guide for Chemists; Academic Press: San Diego, CA, 2000.Thomas, G. Medicinal Chemistry An Introduction; John Wiley & Sons: New York, NY, 2000.Williams, D. A.; Lemke, T.L. Foye's Principles of Medicinal Chemistry; Lippincott Williams & Wilkins: Baltimore, MD, 2002.