KJM5230-H04

Drug Design:Functional groups / Pharmacological Activity

Structure Mechanism of action

Structure Physiochemical properties• Acid / base properties• Water solubility• Partition coefficient• Crystal structure• Stereochemistry

ADME

Absorbtion. Distribution, Metabolism, Excretion(ADMET, ADMEtox)

KJM5230-H04

Structure Mechanism of action

NO

O

OH

ca. 5Å

Acetylcholin (Neurotransmittor)

NO

O

H2N

Carbacholin

N

NH

N

NMe

H

OO

Acetylcholin Agonists

Nicotine Pilocarpine

Protonated av phys. pH (pH≈7.4)

Acetylcholin Antagonists

N

O

O

OH

Atropin

O

O

N

OH

Cyclopentolat

MeO

O

HO

OOH

OMe

NH

Me

NMe

Me

TubocurarinCNS

Effektor celle

Reseptor

Synapse

Acetylkolin

Noradrenalin

Det somatiske nervesystem Det autonome nervesystem

CNS CNS

Det sympatiskenervesystem

Det parasympatiskenervesystem

ganglion

KJM5230-H04

Structure Mechanism of action

SAR: Structure Activity Relationships

Acetylcholine agonists: Small N-quartenary compds.Acetylcholine antagonists: Larger N-quartenary compds.

NCO2Me

O

OCocaine

O

O

N

NH2

Procaine (1905)

NH

N

Lidocaine/Xylocaine(1946)

O

Acid labile ester

HydrophilicAminogroup(can be protonated)

Spacer-Cn-X-X: -CO2- -CONH- -NHCO-

Lipophilic(Aryl)

N

N N

N

R

O

MIC (μg/mL )

R

-H

-CH3

-CH2CH=CH2

-CH2Ph

-SO2Ph

-CH(CH3)Ph

-Ph

-CH2CH2Ph

% Inhibition M. tuberculosis 6.25 μg/mL

6

0

7

>90 3.13

26

12.5

13

14

>90

KJM5230-H04

Structure Physiochemical properties

• Acid / base properties• Water solubility• Partition coefficient• Crystal structure• Stereochemistry

Human body: ca 75% waterpH blood ca 7.4 (physiolog. pH)pH stomach 1 - 3.5pH duodenum ca. 4pH urine ca. 6

Identification of acidic / basic functional groups

pKa determines degree of ionization different places in the body

KJM5230-H04

NO

O

OH

ca. 5Å

Acetylcholin (Neurotransmittor)

Acetylcholin Antagonists Possible atropine analogs?

O

O

N

OH

Cyclopentolat

O

O

N

OHO

O

N

OHO

O

N

OH

O

Cyclopentolate - tertiary amine, pKa ca. 10

[acid form]

[base form]

At pH 7.4

10 = 7.4 + log log[acid form]

[base form]= 2.6

[acid form]

[base form]= 398; 99.75% acid form

O

O

N

OHH = active form

O

O

N

OHH

acid form

+ H20O

O

N

OH

baseform

+ H3O

pKa = pH + log[acid form]

[base form]Henderson Hasselbach

pH=pKa; [acid]= [base]pH<pKa; acid form dominatespH>pKa; basic form dominates

KJM5230-H04

Antibacterial sulfonamides

Old compound

NH2SO

OH2N

Acid form - neutralLow watersol. - crystals - Kidney damage

[acid form]

[base form]

At pH 6 (urine)

10.4 = 6 + log[acid form]

[base form]≈ 25000

Modern compound

ArS

O

O

HN

Sulfametoksasol

pKa 6.1

ArS

O

O

N

- H

+

ArS

O

O

NArS

O

O

N

N

O

N

O

N

O

N

O

ArS

O

O

N

N

O

At pH 6 (urine)

[acid form]

[base form]≈ 1

base form, ionic, water sol.

KJM5230-H04

Structure Physiochemical properties• Acid / base properties• Water solubility• Partition coefficient• Crystal structure• Stereochemistry

Ionisation -permanent charge -acid / base properties

Hydrogen bonds

Ion - dipole bonds

H

N HR

H

Acidic form of amines

H

OH

δ -

δ +

δ +

R

O

O

Basic form of carboxylic acid(carboxylate)

HO

Hδ +

δ + δ -

Intramoleculare interact. reduce water sol.

R

CO2

NH3

Strong intramolec interact.

OH H

OHH

Salts between weak organic acids and weak organic bases does not dissolve well in water

KJM5230-H04

The more H-bonds possible - the more water sol.

RO

HAlchohol

O

HH

H

OH

OH

H

3 H-Bonds

OAldehyde / ketone

HH

OH

OH

2 H-Bonds

R R'

OEster

HH

OH

OH

3 H-Bonds

R OR

HO

H

Primary amine 3 H-BondsR N

H

H

O

O

HO

H

H

H

HH

Secondary amine 2 H-BondsR N

R'

H O

HO

H

H

H

Secondary amine 1 H-BondsR N

R'

R''

HO

H

KJM5230-H04

Prediction of water solubility - Empirical

Water solubilization of functional groups

Functional group Monofunctional comp. Polyfunctional

comp.

Alchohol 5 – 6 carbons 3 – 4 carbons

Phenol 6 – 7 3 – 4

Ether 4 – 5 2

Aldehyde 4 – 5 2

Ketone 5 – 6 2

Amine 6 – 7 3

Carboxylic acid 5 – 6 3

Ester 6 3

Amide 6 2 - 3

Ex. monofuctional comp.methanol - pentanol/hexanol are solubile

Charge: 1 charge - 20-30 C

N

TerbinafineAntifungal agent

21 C-atom, tertiary amine solubilize 6 - 7 C atoms

Insolubile (neutral form)

Corresponding acid (cationic) solubile

(solubile: >10 mg/mL)

KJM5230-H04

Water solubilization of functional groups

Functional group Monofunctional comp. Polyfunctional

comp.

Alchohol 5 – 6 carbons 3 – 4 carbons

Phenol 6 – 7 3 – 4

Ether 4 – 5 2

Aldehyde 4 – 5 2

Ketone 5 – 6 2

Amine 6 – 7 3

Carboxylic acid 5 – 6 3

Ester 6 3

Amide 6 2 - 3

Ex. polyfunctional comp.

Charge: 1 charge - 20-30 C

O

O

NH

OH

BetaxololBetablokker

18 C-atomer

Ether: 2

Ether: 2

Alchohol: 3-4

Amine 2

Tot: 9 - 10

(not solubile)

KJM5230-H04

Prediction of water solubility - Analytical

logP

Experimental: MlogP or logPmeas Calcd: ClogP

P: Partition coefficient between n-octanol and water

Fragment π-value

C (aliphatic +0.5

Phenyl +2.0

-Cl +0.5

-ONO2 +0.2

-S- 0.0

=O C-O- (carboxyl) -0.7

=O C-N- (amide) -0.7

- -O (hydr , oxyl ether) -1.0

N (amine) -1.0

-NO2 (alipha .)t -0.85

-NO2 (aroma .t ) -0.28

O

O

NH

OH

BetaxololBetablokker

12 x C aliphat: +6.0

Ph: +2.0

3 x O: -3.0

N: -1.0

logP +4.0

ClogP (SciFinder): 2.69

π-value: hydrophilic - lipophilic value

logP Rt (HPLC, TLC reverse phease)

KJM5230-H04

Structure Physiochemical properties• Acid / base properties• Water solubility• Partition coefficient• Crystal structure• Stereochemistry

H

HHO

Testosterone

OH

5α-reduktaseH

HHO

5α-Dihydrotestosterone (5DHT)More active A-B ring transCis isomer inaktive

OH

H

10β

5α

A / B trans fused

10β

A / B cis fused

5α

cis-transDiastereomersEnantiomers(Konformers / rotamers)

KJM5230-H04

Biomolecules (reseptors, enzymes): Asymmetric

A

BC

D

Drug

Biomolecular target

Desired responce

D

BC

A

No desired resonceSide effects??

Enantiomers may behave differently:

•Absorbtion (membrane selectivity)

•Metabolism

•Binding to other reseptors than target

(loss, side effects)

•Binding to target reseptor

KJM5230-H04

Restricted rotation - optically active rotamers

P

P

(R)-(+)-BINAP

P

P

(S)-(-)-BINAP

I I

I

NH2

O

CO2H*

Chiral C-atom

Chiral axis (restrict. tot.)4 stereoisomers

X-ray contrast agent

KJM5230-H04

•Screening/Design/Serendipity/Natural products •Lead compound

•Structure Optimisation•Actual Drug

Refinement of lead structure:•Determining pharmacophore•Functional group modification

Pharmacophore: The part of the molecule that contains the functional groups that actually binds to the reseptor

Morfin

O

OHN

OH

N

O

O

Petidine

N

O

O

Dextropropoxyphene

KJM5230-H04

N

N N

N

O

Cl

Lead compoundN

N N

N

Ar

X

Y

Z

Rel high activity

N

N N

N

O

R

R ≠ CH2Ph

N

N N

N

R

R=H, alkyl

Inactive

N

N N

N

Ar

Pharmacophore??

Azapurines??

Deazapurines?? N

N N

Ar

R

??

N

N

Ar

??

Antimycobacterials

??

X

Ar

KJM5230-H04

Improvement of lead by functional group modification

•Activity•Toxicity•Bioavailability•Metabolism

Isosters:Functional groups that results in approx. the same propertiesSteric and electronic similarities

S

bp 81 oC bp 84 oC

-CH=CH- and -S- are isosters

N

bp 116 oC

-C= and -N= not isosters

(at least with respect to bp)

KJM5230-H04

Bioisosters:Functional groups that results in approx. the same biological properties

Classical bioisostersSteric and electronic similarities

Monovalent-F, -H-OH, -NH2

-H, -F, -OH, -NH2, -CH3

-SH, -OH-Cl, -Br, -CF3

Divalent-C=S, -C=O, -C=NH, -C=C-

Trivalente-CH=, -N=

Tetravalente

Rings

N S O

N C

KJM5230-H04

N

N N

N

O

X

-X π σp % Inhib at6.25 μg/mL

MIC(μg/mL )

-H 0 0 >90 3.13-F 0.15 0.06 >90 6.25-OH -0.61 -0.37 79 n. .d-NH2 -1.23 -0.66 23 n. .d-CH3 0.60 -0.17 >90 3.13Bioisosters

σ: electronic effects; σ>0 electr on withdrawi ,ng σ<0 electr on donatingπ: Lipophilicity, π>0 incre asedlipophil. re l t o H

Non-classical bioisostersNot strong steric or electronic similarities

N

N

NNHO

O

N

N

NN

NH

N

O

HO2C

Angiotensin II antagonists(Hypertention)

N

NH

pKa 14.2

N

N

NH

pKa 9.2

N

N

NH

pKa 10.3

N

NN

NH

pKa 4.9 ≈ karboksylsyrer