2. SELECTION OR SYNTHESIS OF HARD
AND 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
3. • 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.
4.
5. • 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
6. • 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
7. 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.
8. 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
9. 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.
10. 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
11. • 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
12. • 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
13. • 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
14. • The simplest example of the soft analog is the
isosteric analog (II) of cetylpyridinium chloride (I)
which is a hard quaternary antimicrobial agent
15.
16. • 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
17. 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
18. • 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
19. Eg: the use of di esters of adrenalone to
deliver the epinephrine the eye via combined
reduction and hydrolysis process .
20. • Soft Drugs based on active metabolite
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.
21. • Eg: Oxyphenbutazone the active p-hydroxy
metabolite of phenylbutazone
• Oxazepam the common active metabolite of
chlordiazepoxide, halazepam, chlorazepate and
diazepam
22. • 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
23. 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
24.
25.
26. References:
Andrejus Korolkovas ESSENTIALS OF MEDICINAL CHEMISTRY, 2ND ED
Friary, 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.
