KJM5230-H06

Drug Design:Functional groups / Pharmacological Activity

Structure - Mechanism of action (Interaction with target)

Structure - Physiochemical properties (Bioavailability etc)• Acid / base properties• Water solubility• Partition coefficient• (Crystal structure)• Stereochemistry

ADME

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

KJM5230-H06

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-H06

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-H06

Active compound identifiedTarget?

Target identifiedLigand?

KJM5230-H06

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-H06

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-H06

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-H06

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-H06

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-H06

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-H06

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-H06

logP

Experimental: MlogP or logPmeas

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)

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

Calcd: ClogP

KJM5230-H06

Absorbtion of Bioactive Compounds

Absorbtion from GI tract

StomachpH 1-3

DuodenumpH 5-7

Jejunum

IleumpH 7- 8

Small intestine

+ digestive enzymes

Drug

GI-tractBlood

Membrane

Acidic / Enzymatic break down

Often rate limiting

Binding to biomolecules

KJM5230-H06

Most drugs: Passive diffusion

StomachpH 1 - 3

Blood

Lipophilic Membrane

R-H R-H

R-CO2H R-CO2H

R-NH3

Amount un ionized drug

pKa pH

pKa = pH + log[acid form]

[base form]Henderson Hasselbach

Low lipophilicity unionized form - low absorbtion

logP - P: Partition coefficient between n-octanol and water Water phase - extracellular fluid

Lipophilic phase - cell membrane

KJM5230-H06

Crossing the membrane

High conc.

Low conc.Chanel protein

Passive transport / diffusion

Rate Conc. absortion site (1. order kinetics)% Drug absorbed lipophilicity

Size of molecule

Certain ionic compounds may go thru as ion-pair

KJM5230-H06

Active transport / Carrier mediated transport

•Less common

•Structural recemblanse with for instance nutritional compound

•Transport against conc. gradient

•Mechanism saturated at high conc.

•Competition for carrier molecules, compounds with structural resemblance

Energy

KJM5230-H06

The Lipinski "Rule of Five"

states that compounds are likely to have good absorption and permeation in biological systems and are more likely to be successful drug candidates if they meet the following criteria:

five or fewer hydrogen-bond donors

ten (2 x 5) or fewer hydrogen-bond acceptors

molecular weight less than or equal to 500

calculated logP less than or equal to 5

*Compound classes that are substrates for biological transporters are exceptions to the rule.

Not too polar

Not too big

Not too hydrophobic

KJM5230-H06

Biomolecules (reseptors, enzymes): AsymmetricEnantiomers may behave differently:

•Absorbtion (membrane selectivity)

•Metabolism

•Binding to other reseptors than target

(loss, side effects)

•Binding to target reseptor

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

A

BC

D

Drug

Biomolecular target

Desired responce

D

BC

A

No desired resonceSide effects??

KJM5230-H06

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-H06

•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-H06

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-H06

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-H06

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-H06

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