THE PRESENTATION GIVES DETAILED EXPLANATION ON PRODRUGS AND HOW TO DESIGN AN PRODRUG.

2. RATIONALE OF PRODRUG DESIGN AND PRACTICAL
CONSIDERATION OF PRODRUG DESIGN
Submitted by
J.ANBU DINESH
M.PHARMACY (PH.CHEMISTRY)

3. CONTENTS
 JOURNEY OF DRUG INVIVO
 PRODRUG
 CLASSIFICATION OF PRODRUGS
 RATIONALE OF PRODRUG DESIGN
 PRATICAL CONSIDERATIONS OF PRODRUG DESIGN
 MARKETED PRODRUGS
 CONCLUSION
 REFERENCE

4. JOURNEY OF DRUG INVIVO 4

5. PRODRUGS
 A prodrug is a chemically inert drug precursor, which upon biotransformation liberates the
pharmacologically active parent compound . It is also called as pro-agent, bio reversible
derivative and congeners.
5

6. IDEAL REQUIREMENT OF PRODRUG
 Prodrugs should be less active or inactive when compared to the parent compound .
 Prodrugs should not posses intrinsic pharmacological activity.
 The carrier molecule released in vivo must be intoxic .
 The linkage between drug and carrier must be cleared invivo.
6

7. CLASSIFICATION OF PRODRUGS
Prodrugs
A) Carrier-linked Prodrugs B) Bio precursors C) Macromolecular Prodrugs
D) Spacer or Linker Prodrugs
(i) Bipartite Prodrugs (ii) Tripartite Prodrugs (iii) Mutual Prodrugs
7

8. A) Carrier-Linked Prodrugs:
A carrier-linked prodrug consists of an active drug temporarily attached to other carrier
with covalent linkage.
The carrier group can be detached enzymatically.
After administration to the body , the prodrug undergoes bio transformations and
converted to the active compound.
8

9. (i) Bipartite Prodrugs
 It is composed of one carrier (group) attached to the drugs.
 Such prodrugs have greatly modified lipophilicity due to the attached carrier.
 The active drug is released by hydrolytic cleavage either chemically or enzymatically.
 E.g. Tolmetin-glycine prodrug.
9

10. (ii) Tripartite Prodrugs
 In tripartite prodrug, the carrier group is attached via linker to drug.
 For example, Prodrug of ampicillin in which the carrier is pivalic acid and linker is –CH2.
Pivampicillin has greater bioavailablity than ampicillin because of the ester group
10

11. (iii) Mutual Prodrugs
 In mutual prodrugs two pharmacologically active compounds are combined and both acts
as promoieties for each other.
 Mutual prodrugs may be of both types bipartite or tripartite.
 The carrier in mutual prodrug may have the same therapeutic action as that of parent drug
or it may have some different therapeutic action which is not shown by parent drug.
11

12. For example, a mutual prodrug of sulbactam and ampicillin (Sultamicillin)
Sultamicillin bears more improved pharmacokinetic properties (ADME) as
compared to alone parent drugs
12

13. (B) Bio Precursors
 Bio- precursor prodrugs produce their effects after in vivo chemical modification of their
inactive form.
 Bio-precursor prodrugs rely on oxidative or reductive activation reactions unlike the
hydrolytic activation of carrier-linked prodrugs.
 They metabolized into a new compound that may itself be active or further metabolized to
an active metabolite
 Oxidation: For example Carbamazipine-10,11-oxide (6), a prodrug of Carbamazepine (5).
13

14. C) Macromolecule Prodrugs:
 In macromolecule prodrugs, the promoiety is a macromolecule like polysaccharides,
proteins, dextrans, cyclodextrins, and polymers etc.
14

15. (D) Spacer or Linker Prodrugs:
 The spacer or linker prodrugs can be used when it is difficult to attach the promoiety with
parent drug directly due to steric hindrance or any other functional barrier.
 The attachment of spacer with promoiety increases the distance between parent drug and
promoiety.
 The spacers are cleaved by enzymatic or chemical action on the bond between promoiety
and spacer.
 For example, Fosphenytoin is a linked prodrug of phenytoin with improved aqueous
solubility.
15

16. RATIONALE OF PRODRUG DESIGN
 (A) Prodrugs having improved water solubility.
 (B) Prodrugs as substrates.
 (C) Prodrugs with improved lipophilicity.
 (D) Chemotherapeutic prodrugs for improved targetability and efficacy.
 (E) Effect of prodrugs on Pre-systemic metabolism and excretion.
 (F) The role of prodrugs for CNS delivery.
16

17. A) Prodrugs having improved water solubility
 The poor aqueous solubility is the major problem as these active agents possess
potential therapeutic activity.
 Prodrug approach helps to overcome the problem of aqueous solubility by
improving dissolution rate.
 Dissolution rate is increased by addition of esters and amides of amino acids and
phosphoric acid.
 Phosphate esters are widely used to increase the aqueous solubility of orally and
parentally administered drugs.
 The amino acid esters and amide prodrugs are also used to improve the aqueous
solubility of active parent drugs
 e.g valacyclovir and valganciclovir which are valine esters of the antiviral drugs
acyclovir and gancyclovir..
17

18. 18
The aqueous solubility of acyclovir is found to be 15-30%, while its valine-prodrug exhibits 50%
aqueous solubility

19. B) Prodrugs as substrates
 The drug has to bypass various pharmacokinetic and pharmaceutical barriers
after administration. To overcome this problem, nowadays site-selective drug
delivery approach is used i.e prodrug design approach.
 The prodrugs act as substrates for various endogenous biological transporters
 e.g Gabapentin enacarbil is a prodrug of gabapentin which is substrate for
monocarboxylic acid transporter-1 (MCT) and Sodium-dependent multivitamin
transporter (SMVT) located all over the intestine.
 Gabapentin enacarbil is having better pharmacokinetic (ADME) properties than
parent drug Gabapentin.
 Other examples are ACE inhibitors, antiviral drugs, and anticancer prodrugs act
as a substrate for (PEPT 1).
19

20. 20
Gabapentin enacarbil is having better pharmacokinetic (ADME) properties than parent drug Gabapentin

21. C) Prodrugs with improved lipophilicity
 The biological membranes consist of phospholipids, therefore, lipophilicity is
required to transport through biological membranes.
 The lipophilicity of polar and ionized drugs can be improved by converting
them into esters.
 The hydrophilic groups present in parent drugs like hydroxyl, thiol, carboxyl,
phosphates and amines can be converted to more lipophilic aryl and alkyl esters.
 These esters can be converted to their active parent drug by the enzymatic
action of esterases.
21

22. 22
For example o-butyryl timolol , a prodrug of timolol having logP/D value of
2.08 while that of timolol logP/D is -0.04.

23. D) Chemotherapeutic prodrugs for improved
Targetability & Efficacy
 Anticancer agents exerts their oncostatic action by inhibition of proliferation and
arresting cell cycle .
 But the oncostatic drugs have poor selectivity in selecting tumour cells, so they
affect normal cells.
 Anticancer prodrug is transported to neoplastic cells and will undergo conversion
to cytotoxic parent drug by local or recombinant enzymes.
 Anticancer drugs are designed to target specific cells as compared to normal cells.
 For improving the specificity of chemotherapy is enzyme-activated prodrug therapy
in which a non-toxic drug is converted into a cytotoxic agents,
 i.e. antimetabolites and alkylating agents.E.g. ADEPT, GDEPT
23

24. Antibody-directed enzyme prodrug
therapy (ADEPT)
 The principle of ADEPT is to use an antibody directed at a tumor-associated
antigen which localizes the enzyme in the vicinity of the tumor.
 A non-toxic prodrug, a substrate for the enzyme, is then given intravenously and
converted to a cytotoxic drug only at the tumor site where the enzyme is
localized, resulting in tumor cell death.
24

25. 25

26. Gene-directed enzyme prodrug
therapy - GDEPT
 GDEPT, is a two-step process.
 In the first step, the gene for a foreign enzyme is delivered to tumor cells.
 In the second step, a non-toxic agent is administered systematically and converted
by the enzyme to its cytotoxic metabolite.
26

27. 27

28. E) Effect of prodrugs on Pre-systemic Metabolism
& Excretion
 The availability of the drug in systemic circulation is affected by pre-systemic
metabolism of the drugs in GIT and the liver.
 Which results in the inadequate quantity of drug at the desired site of action or target.
 This problem has been overcome by altering the route of administration and
development of formulation such as sublingual route and by controlled release
formulations.
 Pre-systemic metabolism can be inhibited by the prodrug approach by masking the
metabolically labile functional groups.
 e.g Terbutaline (used to treat asthma) undergoes rapid pre-systemic metabolism,
therefore, it has been prevented by converting its phenolic groups to Bis-dimethyl-
carbamate (bambuterol).
28

29. Terbutaline to Bambuterol 29

30. F) The role of prodrugs for CNS delivery
 Development of drug across CNS is ineffective due to the decrease capacity of the
drug across the BBB(BLOOD BRAIN BARRIER).
 The passage of drugs across BBB is achieved by intrinsic transporter protein
located at luminal and abluminal cells of epithelial cells.
The Mechanisms by which a compound to enter the brain.
 (a) Increasing the passive diffusion by masking polar groups.
 (b) Increasing the carrier-mediated or receptor-mediated transport through BBB.
 (c) Decreasing the efflux of drug from the brain into the blood.
30

31. 31

32. PRATICAL CONSIDERATIONS
(a) Prodrugs with Esters
(b) Prodrugs with Amides
(c) Prodrugs with Phosphates
(d) Prodrugs with Carbamates
32

33. (a) Prodrugs with Esters
 Esters undergoes hydrolysis easily and has more aqueous solubility compared to
the parent drug.
 For example
 Palmarumycin is a lipophilic drug with poor aqueous solubility and shows poor
anticancer activity in vivo.
 They glycyl-ester derivative of palmarumycin is found to have seven times
increased aqueous solubility than that of parent drug.
33

34. (b) Prodrugs with Amides
 The amide prodrugs are also used for increasing aqueous solubility of parent
drug and its bioavailability.
 Compared to esters, amide bonds are more stable to enzymatic hydrolysis.
 (a) DW2282 (26) is chemically (S)-1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-
indol-6-sulphonyl]-4-phenyl-imidazolidin-2-one, which is an anticancer drug
with low water solubility (0.024 mg/mL) and higher gastrointestinal toxic
effects.
 Many amino acid prodrugs were synthesized almost all of them attained
higher water solubility as compared to the parent drug.
 One of the compound have shown very good aqueous solubility (0.865
mg/mL) and bioavailability by oral route .
34

35. 35

36. (c) Prodrugs with Phosphates
 The phosphate prodrugs have been proven to increase the aqueous solubility and
bioavailability of the parent drug.
 Phosphate prodrugs get converted to its parent drug by the action of intestinal alkaline
phosphatase enzyme.
 A prodrug of benzimidazole derivative α-6-chloro-2-(methylthio)-5-(napthalen-1-yloxy)-1H-
benzo[d] imidazole. (31). The prodrug (32) synthesized by linking disodium phosphate and
found be 50,000-folds higher water soluble than the parent drug.
36

37. (d) Prodrugs with Carbamates
 Carbamates generally exhibits very good chemical and proteolytic stability.
 Carbamates easily permeate through cell membranes and also has the capability to
alter intermolecular and intramolecular interactions within the receptor or enzyme.
 Histone deacetylases are responsible for gene expression and exhibit anti-tumor
activity.
 One of the histone deacetylases inhibitor is a benzamide compound CI-994 (36).The
poor aqueous solubility of this compound is overcomed by addition of two
glucuronide prodrugs.
 In one compound they have linked glucuronide moiety with the aid of spacer (37)
and in another compound they have directly linked the glucuronide moiety with the
carbamate group of parent drug (38).
 The aqueous solubility of parent compound CI-994 was found to be 0.08 mg/mL and
both the prodrugs showed aqueous solubility more than 1 mg/mL.
37

38. 38

39. MARKETED PRODRUGS 39

40. CONCLUSION
 The process of drug discovery and development is time-consuming & costly are
overcomed by the process such as computer-aided drug design (CADD),
combinatorial synthesis by focussing on various pharmacokinetic,
pharmacodynamic properties of the drug.
 Prodrug design helps to enhance the therapeutic efficacy of the parent drug and
reduces toxicity.
 The prodrugs are now used to improve aqueous solubility, lipophilicity and also to
improve target-selectivity by various mechanisms such as by transporter proteins
(SLC & ABC transporters) and by enzyme activated prodrug therapy (ADEPT &
GDEPT).
 It is not always easier and faster to develop prodrugs.
 For the future research scope and successful prodrug approach, more studies are
needed to identify more novel prodrug structures (promoieties) to target desirable
tissues and to achieve desired pharmacological action
40

41. REFERENCES
 1) An Introduction to Medicinal Chemistry by Graham L. Patrick Second Edition pg no: 239-259
 2) Dr. M.S Rathore et al. Prodrug Design and Development for Improved Bioavailability across
Biological Barriers published on Human Journals September 2016 Vol.:7, Issue:2
 3) Supriya Shirke, Sheetal Shewale and Manik Satpute, Prodrug Design: An
Overview,International Journal of Pharmaceutical, Chemical and Biological Sciences, 5(1), Pg. No. 232-
241, 2015.
 4) Kristiina M. Huttunen, Hannu Raunio, and Jarkko Rautio, Prodrugs—from Serendipity to
Rational Design, Pharmacological Reviews, Vol. 63, No. 3, Pg. No. 750–771, 2011.
41

42. 42