Download 1 Thus , Knowledge of physicochemical properties

Medicinal Chemistry 1
Introduction to medicinal chemistry
Areej Abu Hammad , PhD
G
oal of medicinal chemistry study is to
Find the treatment for several diseases , this
requires to specify a target that's
responsible for the illness and a suitable
designed drug.
The 11th lecture
Sun. 20th of October,2013
Aya Alghazal
By these three methods we:
Optimize the drug interaction with the
receptor.
Targets used to be proteins, enzymes, receptors,
and other new targets like DNA.
The process of designing a drug for a certain target
is indirect, it's summarized as:-
Identifing
Develping
Optimize the access to the target (the effect
further to binding).
• Start with a search to identify
an initial Lead of a drug.
Increase the resistance to chemical and
enzyme degradations , in other words it's
needed to have a stable drug upon
• Develop this Lead to a finished
optimized drug molecule.
administration and full interaction period.
Thus , Knowledge of physicochemical properties
(PKa , Solubility…) , electronic properties
(ionization…) , 3D shape (perform interaction
forces with the target and provides a structural fit)
and stereochemistry (because proteins are very
selective and protective) of the drug is required.
Avoid poisonous effect by ensuring the
ability for degradation , metabolism and
elimination.
Targeting the drug and direct it for the
infected organ to minimize side effects and
toxicity.
By understanding of these properties, three
methods can be used to design the drug:
Bioisosteric
replacement
Conformational
restriction
Prodrug
formation
•find the desired
property of the drug
in order to bind to a
certain receptor and
make a bioisosteric
replacement for it.
•by controlling
the structure.
► Flu , Influenza is a very common widespread
disease , if the aim was to treat the disease itself
not only it's symptoms an Antiviral is needed , such
as Tamiflu.
♦ Tamiflu:
♦ it's generic name is Oseltamivir phosphate ,
prepared as salt to enhance it's solubility which in
turn is important for the absorption and kinetics , as
long as the salt formation is reversible (not a
covalent bond) it should be ionized in solution.
♦ Administered orally or as suspension , so it
possess Oral Bioavailability (considering that not all
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Medicinal Chemistry 1
Introduction to medicinal chemistry
Areej Abu Hammad , PhD
Drugs have this property if only given for example
as inhalation , parentral …)
◊ What determines if the drug has oral
bioavailability or not is if it's absorbed or
not in
GIT.
◊ Physicochemical properties that's responsible for
this property are : water solubility, lipophilicity
(for absorption) by which there's balance between
them.
♦ It's a prodrug ; administered inactive and become
activated in the body by enzymatic activation "
degradation of a certain bond " this group is the
ester bond , because it's a very reversible bond and the
human body has many estrases.
◊ other common groups used in prodrugs are
amides but esters are more common.
◊ Note that we didn't say that the phosphate is the
group used for prodrug preparation , instead it's
used only for salt formation and upon exposure to
aqueous media it dissociates readily.
The 11th lecture
Sun. 20th of October,2013
Aya Alghazal
♦ Mechanism of action: binds to the viral
neuraminidase enzyme , this enzyme is a
glucosidase cleaves a glycosidic bond of the sialic
acid ( neuraminic acid) moiety , this enzyme is
responsible for the release of viruses that's attached
to certain structures from the host cell, if we block
it, viruses will get stock in the cell and neither
release nor spreading of the disease will happen ,
so Tamiflu treat and prevent the infection.
♦ Neuraminidase enzyme is a protein with a
globular structure.
♦ Used for Influenza A and B viruses , thus it has
a broad-spectrum activity , if it was effective for only
one microorganism we would say it's very
selective.
♦ The advantage of it's Oral use is the more
convenient use ( better than three parentral doses per
day for a cold for example).
♦ Given twice daily >> the half life , elimination
rate , Liver / Kidney function determine the dosing.
♦ Elimination process can be either renal excretion
(passive or active) or metabolic degradation ( by
liver ).
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