DESIGNING CARRIERLINKED PRODRUGS

1
DESIGNING CARRIER-LINKED PRODRUGS
Carrier-mediated prodrugs are designed with
specific applications in mind

• to improve lipophilicity

• to improve hydrophilicity

• to improve site-selective delivery

• to solve chemical formulation problems

2
Lipophilic Carrier Prodrugs
estradiol prodrug
dipivefrin
naproxen-2-glyceride prodrug
3
Hydrophilic Carrier Prodrugs
in vivo
in vivo
chemical
chemical
4
Hydrophilic Carrier Prodrugs
Clindamycin (Dalacin)
phosphate palmitate
5
Site-Selective Carrier Prodrugs
selective renal vasodilation with ?-glutamyl-DOPA
Dopamine
gamma glutamyl transpeptidase

Glutamic acid

DOPA decarboxylase
CO2
6
Prodrugs and Formulation Problems
chloramphenicol palmitate
chloramphenicol
CH3CH2 - SH
ethanethiol
7
Prodrugs and Formulation Problems
chloral hydrate
chloral
trichloroethanol
8
BIOPRECURSORS
The Active Metabolite Concept
9
BIOPRECURSORS
proguanil
cycloguanil
10
DESIGNING BIOPRECURSORS
GABA
pyrroline
GABA precursor
pro-2-PAM
site-selective delivery to brain
2-PAM
11
DESIGNING BIOPRECURSORS
1. N-dealkylation
2. ring closure
X H (alprazolam) Cl (triazolam)
in vivo conversion to benzodiazepines
12
DESIGNING BIOPRECURSORS
sulindac
reductive bioactivation of sulindac
13
DESIGNING BIOPRECURSORS
5-oxo-L-prolinase
L-glutamic acid
5-oxo-L-proline
1
4
2
L-cysteine
L-2-oxothiazolidine-4-carboxylate
intracellular cysteine delivery system
14
MIXED-TYPE PRODRUG
brain
systemic circulation
X O, N
BBB
selective drug delivery system to brain
15
cholesterol
spacer
targetor
peptide
passive transport through BBB
oxidation
16
enzymatic removal of cholesterol
enzymatic release of peptide
YAGFL
YAGFL
enkephalin
17
LIMITATIONS OF THE LATENTIATION CONCEPT

• Formation of a toxic prodrug (carrier-mediated)
  metabolite which is not produced from the drug.

• Consumption of a vital endogenous component (e.g.
  glutathione) during metabolic process.

18
LIMITATIONS OF THE LATENTIATION CONCEPT

• Generation of a toxic metabolite from the inert
  carrier moiety.

• Release of an endogenous modifier (causing enzyme
  induction, altered drug excretion, displacement
  of protein-bound compounds, etc.).

19
HARD DRUGS
Basic principles of hard drug design

• to minimize metabolism

goal?

• minimize intra- and interindividual variability

benefit?

• reduce possibility of toxic metabolites

• possibly increase half life

20
HARD DRUGS
How is goal (minimize metabolism) achieved?

• block metabolically labile functional group

excretion
21
HARD DRUGS
How is goal (minimize metabolism) achieved?

• block metabolically labile position

excretion
22
HARD DRUGS
tolbutamide
hard drug
chlorpropamide
23
SOFT DRUGS
Basic principles of soft drug design

• soft drug is analog or isostere of a lead drug

• metabolically labile site built in

• metabolically labile site is in noncritical area

• metabolically labile site is major metabolic route

• Metabolic products are non-toxic and inactive

24
SOFT DRUGS
cetylpyridinium chloride
isosteric soft drug
25
SOFT DRUG DESIGN
Atracurium