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PharmDr. Pavol Ježko, PhD. Department of Pharmaceutical ChemistryFaculty of Pharmacy, Comenius UniversityOdbojarov 10, 832 32 Bratislava, Slovakia
Tel: + 421 250 117 395
e-mail:
jezko@fpharm.uniba.sk
;^ p.jezko@gmail.com
-^
-^
pharmacology, biochemistry, molecular biology, imunology(life sciences)
-^
organic, physical, theoretical chemistry, molecular spectroscopy,crystallography, (chemical sciences)
-^
information technology
Three mainThree main phases of
phases of drug action
drug action
-^
pharmaceutical phase
release of drug from the drug form
-^
pharmacokinetic
phase
(wh
at
makes
the body
with the drug)
-^
pharmacokinetic
phase
(wh
at
makes
the body
with the drug)
ADME
-^
pharmacodynamic phase
(what makes the drug with the organism)
character and quality of drug interactionswith interaction site of the biological system
Basic terms in pharmaceutical chemistry
-^
(biomacromolecule to interfere with)
BINDING POCKET – ACTIVE SITE (part of the target appropriate to bind a small ligand)
-^
(a part of a molecule that is recognized at a receptor site and is
responsible for that molecule's biological activity)
-^
organic molecule possessing target affinity, that has to be stereo-
electronically compatible with binding pocketelectronically compatible with binding pocket^
is a compound detected by usually HTS
is a active compound identified in a screen with
confirmed structure and
activity
, that need to be developed into lead compound
is a
active
compound
with convenient properties
: drug-likeness,
solubility, synthetic feasibility, patentability
high activity, good selectivity,
in vivo efficiency
after success in clinical trials
approved
by FDA, EMEA
DRUG-LIKENESS complex properties^ –
ADME/Tox
bsorption/
D istribution/
etabolism/
E xcretion/
T oxicity)
PharmaceuticalPharmaceutical chemistry
chemistry includes
includes:
:
TheThe process
process of
of discovery
discovery = identification and production
of new active compounds^
-^
The optimization process^
-^
The development process^
A) The Natural World
Micro-organisms
(bacteria, fungi)
Marine
chemistry
(corals, bacteria, fish etc)
Plant
life
(flowers, trees, bushes)
Animal
life
(frogs, snakes, scorpions)
Biochemicals
(neurotransmitters, hormones)
Pure natural products, bioextracts
(e.g. plant, or
microbial)
Ethnopharmacology
(Chinese
From were to get active compounds? B) The Synthetic World C) The Virtual World
microbial)
Ethnopharmacology
(Chinese
traditional medicine...) LMW synthetic compounds (traditional, combinatorial synthesis, historicalcorporate chemical collections, commercialsources)^ Computer
aided drug design (CADD)
to call them „active compounds“ evaluation through biological screening is essential
Structure – activity relationship
-^
primary task of the medical chemist is to identify leading sceleton and itssubsequent modification in order to obtain a suitable candidate to drug thatmay be introduced into clinical practice
-^
leading structure may have some deficiencies, chemical and biologicalcharacteristics: a lack of specificity, low activity, metabolic, chemical instability, high toxicity, low bioavailability, poor solubilityinstability, high toxicity, low bioavailability, poor solubility
-^
irrational approach: make all the easy and available variations of the leadingsceleton
-^
rational process: methods and approaches that describe the relationshipbetween drug structure and its activity- knowledge of the spatial (3D) structure of the receptors at atomic levelresolution)- knowledge of the conformation of ligands and their interaction with target macromolecules
StrategiesStrategies of
of modification
modification existing
existing structures
ructures
-^
by chemical modification will be prepared newcompounds, which will have higher activity,
lower toxicity,
or
better
dosage form
activity,
lower toxicity,
or
better
dosage form
Classical bioisostersClassical bioisosters
Are of similar size, shape and valence electron configuration Classical isosters that can serve as bioisosters:^ monovalent atoms and groupsA: –CH
3
2
–OH –F –Cl
Cl
2
bivalent atoms and groupsA: –CH
–Se–
Cl
2
C: –Br –
i -Pr
t -Bu
ring equivalentsA: –CH=CH–
(benzene; tiophene)
(benzene; pyridine)
(tetrahydrofurane; tetrahydrotiophene;cyclopentane; pyrrolidine)
trivalent
tetravalent
Si<
–As=
NonclassicalNonclassical bioisosters
bioisosters
-^
Are of different numberof atoms, do not meetthe steric and electronrules of classicalbioisosters, but evokesimilar biological activity
O R R
R R^
CN CN
S^
O R R
OR S OR
R^
SO
2
R N R
R^
CH CN^ R
COOHCONHCNPO(OH)OEt
SO
NHR 2 CONHOHPO(OH)NH
SO 2
H 3
O^
N
OH
O
O OH
N N
N N
CH 3 H
R^
COO
R
N R^
R^
S R^
R
NOMe R
Nonclassical bioisosters of Carbonyl groupNonclassical bioisosters of Carboxyl groupNonclassical bioisosters of Ester group
14
R^
COO
R
N^
O^
N
NOMe R
R^
CONH
R
R^
CONMe
R
R^
CSNH
R
R^
CH
NH 2
R
C^
C R R^
R^ R R
CH
S^2
R
R^
OH
R^
NHCOR
R^
NHSO
R^2
R^
CH
OH 2
R
NHCONH
R 2 NHCN
R
CH(CN)
OH OH
N NH
X
O OH^ X = O, NR
N O OH
Nonclassical bioisosters of Amide groupNonclassical bioisosters of Hydroxyl groupNonclassical bioisosters of Catechol groupNonclassical bioisosters of Halogen Halogen
CF
3
CN
NCN
2
C(CN)
3
Nonclassical bioisosters of Urea-like NHC(=S)NH
2
NHC(=NCN)NH
2
NHC(=CHNO
)NH 2
2
-^
systematic testing of new compounds withoutthe known mechanism of action andpharmacological potential
-^
extensive screening
a
comprehensive
-^
extensive screening
a
comprehensive
pharmacological assessment is subjected to alimited number of “advanced“ structures
-^
random screening - from large number ofcompounds (hundreds-thousands) is looking forone which is active in the indication
The use of biological information
-^
monitor the effects of random compounds fornew discoveries about biological processestaking place in biology and medicine^ –
observation of people - folk medicine (Digitalis,opiates, quinine, atropine, cocaine)
observations in animals - in vivo pharmacologicaltests on animals (Vinca rosea - vincristine,vinblastine)
-^
-^
-^
