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Pharmaceutical Pharmaceutical
(medicinal) (medicinal)
chemistrychemistry
IntroductionIntroduction
1
PharmDr. Pavol Ježko, PhD.
Department of Pharmaceutical Chemistry
Faculty of Pharmacy, Comenius University
Odbojarov 10, 832 32 Bratislava, Slovakia
Tel: + 421 250 117 395
e-mail: jezko@fpharm.uniba.sk;p.jezko@gmail.com
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PharmaceuticalPharmaceutical

(medicinal)(medicinal)

chemistrychemistry

IntroductionIntroduction

1

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

DefinitionDefinition of

of pharmaceutical

pharmaceutical chemistry

chemistry

-^

pharmaceutical chemistry^ –

discovery

development

identification and interpretation of the mode of action of^ biologically active compounds

at the molecular level

biologically active compounds

at the molecular level

-^

pharmaceutical chemistry is an

interdisciplinary

science

•^

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

(biopharmaceutical)



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

-^

TARGET

(biomacromolecule to interfere with)

•^

BINDING POCKET – ACTIVE SITE (part of the target appropriate to bind a small ligand)

-^

PHARMACOPHORE

(a part of a molecule that is recognized at a receptor site and is

responsible for that molecule's biological activity)

-^

LIGAND

organic molecule possessing target affinity, that has to be stereo-

electronically compatible with binding pocketelectronically compatible with binding pocket^ 

ACTIVE

is a compound detected by usually HTS

HIT

is a active compound identified in a screen with

confirmed structure and

activity

, that need to be developed into lead compound

LEAD

is a

active

compound

with convenient properties

: drug-likeness,

solubility, synthetic feasibility, patentability 

DRUG CANDIDATE

high activity, good selectivity,

in vivo efficiency

DRUG

after success in clinical trials

approved

by FDA, EMEA

•^

DRUG-LIKENESS complex properties^ –

ADME/Tox

:^ A

bsorption/

D istribution/

M

etabolism/

E xcretion/

T oxicity)

PharmaceuticalPharmaceutical chemistry

chemistry includes

includes:

:

  • •^

TheThe process

process of

of discovery

discovery = identification and production

of new active compounds^ 

natural resources
synthesis
biotechnology
design -
computer aided drug design (CADD)

-^

The optimization process^ 

synthetic modification of the lead sceleton (structures) toimprove the effect , selectivity and suppress toxicity (S.A.R.)

-^

The development process^ 

optimization of synthetic processes for mass production of thedrug
modification of pharmacokinetic properties of thedrug (suitable for clinical use)

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

–NH

2

–OH –F –Cl

B:

Cl

PH

2

– SH

bivalent atoms and groupsA: –CH

–NH–
–O–
–S–

–Se–

B:
COCH
CONH
–^
– COO
–^
– COS
B:

Cl

PH

2

– SH

C: –Br –

i -Pr

D: –I –

t -Bu

B:
COCH
CONH
–^
– COO
–^
– COS

ring equivalentsA: –CH=CH–

–S–

(benzene; tiophene)

B: –CH=
–N=

(benzene; pyridine)

C: –O– –S– –CH
– –NH– 2

(tetrahydrofurane; tetrahydrotiophene;cyclopentane; pyrrolidine)

trivalent

tetravalent

A: –CH=
–N=
A: >C<

Si<

B: –P=

–As=

B:
=C=
=N
=P

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

SystematicSystematic screening

screening

-^

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)

GeneticsGenetics,

, genomics

genomics

andand drug

drug development

development

-^

Over the last 15 to 25 years there has been progress inseveral scientific fields, particularly combinatorialchemistry, genomics, proteomics and bioinformatics,which are promise for the future in a streamlining of procedures

discovering new drugs.

procedures

discovering new drugs.

-^

The main idea of new methods of research and drugdevelopment is to identify the biological action, gene orprotein that is disrupted in the disease process.

-^

Then, on the basis of this knowledge could be design adrug that specifically interact with the site of action

Computational

pharmaceutical chemistry