3. Targeted Delivery of the Drug
• Targeted drug delivery system have been desgined on the concept of
magic bullets given by Dr. Paul Ehrlich
• This concept is associated with the development if such systems which
when introduced in the body , dirct the drug only to its site of action
therpy providing maximum theraputic response with reduced toxic effect
to decrese distrbution of other body tissue .
• Targeted drug delivery may be achieved by physical, biological, and
molecular systems that provide high concentrations of the active agent at
the pathophysiologically relevant sites.
• Many drugs have poor receptor specifcity resulting in side-effects that
may or may not be due to the specifc.
• substrate±receptor interactions involved in the desired drug action. The
receptors also may be distributed throughout the body besides those
present at the target site. Consequently, drug targeting should include
many considerations other than the improvement of receptor±substrate
interactions by re®ning the molecular architecture, such as molecular
transport and other related processes
4. • The blood-brain barrier (BBB), an important biological membrane in
the body, has been a perennial obstacle to the development of
drugs that act directly on the central nervous system (CNS).
• The capillaries in more than 99% of the brain parenchyma possess
tight, high-resistance junctions between the endothelial cell.
• The capillaries in more than 99% of the brain parenchyma possess
tight, high-resistance junctions between the endothelial cells.1,2
The cells themselves lack ``pores'' for the diffusion of water soluble
molecules, and pinocytic vesicles are largely absent.3 Towards small
molecules, the brain capillary endothelium behaves like a
continuous lipid bilayer, and diffusion is largely dependent on the
lipid solubility of the solute. Intracellular or transcellular transport,
i.e., directly through the endothelial cell membrane, is the principal
route into and out of the CNS for most drugs.4 Therefore, the BBB is
generally permeable to lipophilic compounds, but excludes
hydrophilic molecules
5. • The physicochemical restrictions discussed above prevent
the entry of many potentially useful drugs into the CNS.
While a peripheral cancer, for instance, may be effectively
treated with a particular drug, central metastasis of this
cancer is usually refractory to similar treatment.
• The potential neuropharmaceutical use of biotechnology-
based therapies, such as various neuropeptides, is also
hampered. Transport of peptide molecules across the BBB
may occur, but it is unlikely that endogenous peptides pass
the BBB in physiologically signi®cant amounts. Although
peptide molecules may actually reach the cellular elements
of the tissue within the circumventricular organs, there is
no evidence of penetration to deeper layers.
• Most of the naturally occurring neuropeptides are
hydrophilic and, thus, do not cross the BBB in the absence
of a specifc transport system in the BBB
6. Method to improve the conc of the
drug in the brain
• General methods for improving the efflux of
medication into the brain have relied on various
approaches which have recently been reviewed
extensively.
• One method for selectively increasing brain
concentrations of therapeutic agents is by their
direct injection into the cerebrospinal fluid (CSF).
• Medication can be administered intrathecally (i.t.)
or intracerebroventricularly (i.c.v.) at one of three
sites including the lumbar area, the basal cistern,
or the ventricles
7. • In these indications, many drugs of choice are
highly water soluble, and are therefore excluded
from the brain. Unfortunately, i.t. administration
is associated with many medical risks, some of
which are unacceptably high,22 including
encephalitis, meningitis, and arachnoiditis. In
addition, the method itself is often ineffcient.
• Since polar drugs administered into the CSF are
restricted to this aqueous compartment, their
distribution is uneven and incomplete in the CNS.
Also, the rate of drug distribution is usually
dependent on the rate of CSF flow, and as such, it
is often slow.
8. • A second method involves the disruption of the BBB via
carotid infusions of hypertonic aqueous
nonelectrolytes.25,26 The mechanism of the transient BBB
disruption involves an osmotic shrinkage of endothelial
cells, which opens the normally tight junctions.27,28
Compounds that have been used include glucose, sucrose,
arabinose, and urea. This method results in an
indiscriminate delivery. The considerable toxic effects of
the procedure should also be taken into account.
Inflammation, encephalitis, and seizures (as high as 20% of
the applications) have been reported. Altogether, BBB
disruption and i.t. administration are invasive techniques,
and their use is only justifed in life-threatening medical
conditions
9. Classification of Noninvasive brain-
delivery systems
• 1- biological approaches
• 2- chemical approaches
Biological systems involve cellular drug carriers.
Brain-targeting strategies have been proposed
based on specifc peptide transcytosis systems
that exist for various biomolecules in the BBB
10.
11. Chemical approaches
• Chemical apporaches to improve brain uptake
of a therapeutic agent rely on molecular
manipulations.
• Prodrug formation involves a transient
chemical modifcation of the pharmacologically
active species to improve the defcient
physicochemical properties.
12. • A prodrug is a pharmacologically inactive
compound that can be converted to the
parent drug usually by a single activating step.
In order to improve the entry of a hydroxy,
amino or carboxylic acid±containing drug,
esterifcation or amidation may be performed
to increase the lipophilicity of the target
compound.
13.
14. Limation
• Unfortunately, most prodrugs have several important limitations in
drug targeting. While increasing the lipophilicity of a molecule may
improve its movement through the BBB, the uptake of the
compound into other tissues is likewise increased leading to a
generally greater tissue burden. This nonselective delivery is
especially detrimental when potent drugs such as steroids or
cytotoxic agents are considered
• In addition, while the uptake of the prodrug into the CNS may be
facilitated by the increased lipophilicity, its ef¯ux is also enhanced
resulting in poor tissue retention (In general, lipid-soluble
compounds that are able to cross the BBB can maintain active
concentrations in the CNS only if their blood concentrations are
maintained at adequately high levels)
• Finally, while the only metabolism process involving the prodrug
should be its conversion to the parent drug, other routes can also
occur and may contribute to the toxicity of the compound.
15. • Some of the weaknesses of the prodrug approach
originate in the single chemical conversion
occurring in the activation of the compound.
Multiple conversions may not only lead to
selectivity in delivery under certain conditions,
but also decrease the toxicity of a drug and to
sustain its action.
• The recognition of this important aspect led to
the concept of chemical delivery systems (CDSs).
16. Desiging of CDS
• In designing a CDS for the CNS, the unique
architecture of the BBB can actually be turned
to an advantage. First, a CDS should be
suffciently lipophilic to enter the central
compartment. The molecule should then
undergo an enzymatic and/or chemical
conversion to promote retention in the CNS. It
is expected that, at the same time, peripheral
elimination of the entity is accelerated due to
facile conversion of the CDS in the body
17. • It is expected that, at the same time,
peripheral elimination of the entity is
accelerated due to facile conversion of the
CDS in the body. CDSs that possess these
attributes have been developed in which a
hydroxy, amino or carboxylic acid containing
drug is covalently linked to a functional group
containing a dihydropyridine unit that serves
as a redox ``targeter'' (T).
18. B R A I N - T A R G E T I N G B Y D I H Y
D R O P Y R I D I N E
19. Design and Mechanism of Action
• A CDS is defned as a biologically inert molecule that
requires several steps of chemical and/or enzymatic
conversion to the active drug and enhances drug
delivery to a particular organ or site.
• In designing a CDS for the CNS, the existence of the
BBB is actually exploited, as shown in Fig. 1. Tis a
specifc functional group attached to the molecule
which, in addition to enhancing BBB penetration by
virtue of its lipophilicity, can be converted by enzymatic
oxidation to a water soluble, lipid insoluble, quaternary
pyridinium salt (T‡
+).
20. • The drug molecule (D) may be further modi®ed to provide
increased lipophilicity through biolabile functional groups (F1,...,Fn)
which are susceptible to easy removal. Upon systemic
administration, the CDS can partition into several body
compartments due to its enhanced lipophilicity, some of which are
inaccessible to the unmanipulated compound. At this point, the
CDS is simply working as a lipoidal prodrug. However, the
dihydropyridine-type T moiety, undergoes an enzymatically-
mediated oxidation and converts to a membrane-impermeable
pyridinium salt. At this point, the CDS is simply working as a lipoidal
prodrug. However, the dihydropyridine-type T moiety, undergoes an
enzymatically-mediated oxidation and converts to a membrane-
impermeable pyridinium salt. This conversion occurs ubiquitously.
The mechanism of this oxidation has been extensively examined
21.
22.
23. Introduction
• The pyridine moiety has found a function in almost all aspects of organic
chemistry, as a solvent, base, ligand, functional group, and molecular scaffold.
• As a structural element, pyridine is considered a privileged pharmacophore in
medicinal chemistry.
• Each containing an intact pyridine moiety—Takepron, Nexium, Singulair, and Actos
produced billions of dollars in revenue in 2010. (Scheme 1).
24. • Modern C-H activation methods have confirmed pyridine as an essential functional
group with unique directing and activating utility.
• The crucial chelating ability of pyridine has given the molecule an important role in
metal organic frameworks and other supramolecular structures hJA10756,
JA14457, JA15814, CC8752i.
• Pyridinium salts are versatile reagents and important cationic structures in
nanodevices hCSR2203, EJO92i.
• Pyridines have found applications in organoelectronic materials hCEJ2392i, organic
light-emitting diodes technology hOL5534i, herbicides hJHC171i, and molecular
sensors hJA8544, CEJ1480i.
• Even as the forefront of nano- and biotechnology calls on chemists to prepare
innovative pyridine-derived structures, novel alkaloids containing the pyridine
moiety continue to be uncovered in nature.
25. • Polyaxibetaine (Scheme 2) is a modified tyrosine that contains a pyridine moiety
. Isolated from the skin of the poison arrow frog Epipedobates anthonyi,
phantasmidine is a tightly wound knot of fused ring systems containing a
chloropyridine, dihydrofuran, pyrrolidine, and cyclobutane.
* Dedicated to the late John Daly, this novel ring system shows activity as a nicotinic
acetylcholine receptor agonist but with different selectivity than Daly’s epibatidine.
*Lycoposerramine is a member of the pyridine-containing lycodine family of alkaloids
and was recently synthesized for the first time in 2010
26. • Isolated from the Australian colonial ascidian
Aplidiopsis confluata, aplidiopsamine
• A contains a fused pyrrolo[2,3-c]quinoline
linked to an adenine residue (Scheme 3).
• The compound shows significant anti-
plasmodial activity even against
chloroquineresistant parasites
27. Preparation of Pyridines
• Cyclocondensation-based syntheses have historically been the most commonly
used preparations of pyridine.
