Download Structure Mechanism of action

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
Acetylcholin
(Neurotransmittor)
ca. 5Å
Acetylcholin Agonists
O
O
Pilocarpine
Nicotine
Carbacholin
Me
N
O
N
H2N
N
N
O
O
H
N
O
H
O
N
H
Protonated av phys. pH (pH- 7.4)
Det somatiske nerves ystem
Det autonome nervesys tem
CNS
Det sympatiske Det paras ympatis ke
nervesystem
nervesystem
CNS
CNS
Acetylcholin Antagonists
Atropin
N
N
H
MeO
ganglion
N
OH
Acetylkolin
Noradrenalin
Tubocurarin
Cyclopentolat
OH
O
Me
O
O
O
HO
O
Synapse
O
OH
Me
Reseptor
N
Effektor celle
Me
KJM5230-H04
OMe
Structure  Mechanism of action
SAR: Structure Activity Relationships
Acetylcholine agonists: Small N-quartenary compds.
Acetylcholine antagonists: Larger N-quartenary compds.
O
N
N
N
N
N
CO2Me
NH2
O
Cocaine
O
O
N
O
R
N
H
O
Procaine
(1905)
N
R
Lidocaine/Xylocaine
(1946)
% Inhibition M. tuberculosis
6.25 g/mL
-H
6
-CH3
0
-CH2CH=CH2
7
MIC
(g/mL)
Acid labile ester
Hydrophilic
Aminogroup
(can be protonated)
Spacer
-Cn-XX: -CO2-CONH-NHCO-
Lipophilic
(Aryl)
-CH2Ph
>90
-SO2Ph
14
-CH(CH3)Ph
KJM5230-H04
>90
-Ph
13
-CH2CH2Ph
26
3.13
12.5
Structure  Physiochemical properties
•
Acid / base properties
•
•
•
•
Water solubility
Partition coefficient
Crystal structure
Stereochemistry
Human body: ca 75% water
pH blood ca 7.4 (physiolog. pH)
pH stomach 1 - 3.5
pH duodenum ca. 4
pH urine ca. 6
Identification of acidic / basic functional groups
pKa determines degree of ionization different places in the body
KJM5230-H04
Acetylcholin
(Neurotransmittor)
Possible atropine analogs?
Acetylcholin Antagonists
ca. 5Å
N
N
N
O
OH
O
O
O
O
O
OH
OH
OH
O
O
N
N
O
O
O
O
Cyclopentolat
H
Cyclopentolate - tertiary amine, pKa ca. 10
pKa = pH + log
[acid form]
Henderson Hasselbach
[base form]
H
N
N
OH
O
+ H3O
OH
+ H20
O
O
O
acid form
baseform
pH=pKa; [acid]= [base]
pH<pKa; acid form dominates
pH>pKa; basic form dominates
At pH 7.4
10 = 7.4 + log
[acid form]
[base form]
log
[acid form]
= 2.6
[base form]
[acid form]
= 398; 99.75% acid form
[base form]
H
N
= active form
OH
KJM5230-H04
O
O
Antibacterial sulfonamides
Old compound
At pH 6 (urine)
10.4 = 6 + log
[acid form]
[acid form]
[base form]
[base form]
O
H2N S
O
- 25000
NH2
Acid form - neutral
Low watersol. - crystals Kidney damage
Modern compound
O
N
O
O
- H+
HN S Ar
O
Sulfametoksasol
pKa 6.1
N
O
N S Ar
O
O
O
N
N
O
N S Ar
O
O
N S Ar
O
At pH 6 (urine)
[acid form]
O
N
base form, ionic, water sol.
O
N S Ar
O
KJM5230-H04
[base form]
- 1
Structure  Physiochemical properties
Ion - dipole bonds
•
Acid / base properties
•
Water solubility
Ionisation
•
•
•
Partition coefficient
Crystal structure
Stereochemistry
Hydrogen bonds
+
+
H
H
+ O H
+
Acidic form of amines
H
O
H
O
R N H
H
Intramoleculare interact. reduce water sol.
H
H
- O
-permanent charge
-acid / base properties
R
CO2
O
Strong intramolec interact.
R
Basic form of carboxylic acid
(carboxylate)
NH3
H
O
H
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.
H
H
O
O
H
Alchohol
H
R
O
H
H
H
3 H-Bonds
H
O
H
O
H
Primary amine
R
H
H
O
H
H
3 H-Bonds
O
H
2 H-Bonds
O
R
O
H
H
O
Aldehyde / ketone
H
N H
R'
Secondary amine
R'
R
H
N H
O
2 H-Bonds
H
H
H
O
O
H
H
Ester
3 H-Bonds
O
R
H
O
H
R'
Secondary amine
R
1 H-Bonds
N R''
R
H
H
O
O
H
KJM5230-H04
O
H
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
Amin e
6–7
3
Carboxyli c acid
5–6
3
Ex. monofuctional comp.
methanol - pentanol/hexanol
are solubile
Terbinafine
Antifungal agent
N
21 C-atom, tertiary amine solubilize 6 - 7 C atoms
Insolubile (neutral form)
Ester
6
3
Amid e
6
2-3
Charge: 1 charge - 20-30 C
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
Ex. polyfunctional comp.
Betaxolol
Betablokker
O
OH
2
Ether:
2
Alchohol: 3-4
Ketone
5–6
Amin e
6–7
3
Carboxyli c acid
5–6
3
Ester
6
3
Amid e
6
2-3
Charge: 1 charge - 20-30 C
N
H
Ether:
2
Amine
2
Tot:
9 - 10
O
18 C-atomer
KJM5230-H04
(not solubile)
Prediction of water solubility - Analytical
logP
P: Partition coefficient between n-octanol and water
Experimental: MlogP or logPmeas
Calcd: ClogP
logP  Rt (HPLC, TLC reverse phease)
Fragment
-value
C (aliph atic
+0.5
Phenyl
+2.0
-Cl
+0.5
-ONO2
+0.2
-S-
0.0
O=C-O- (carboxyl)
-0.7
O=C-N- (amide)
-value: hydrophilic - lipophilic value
Betaxolol
Betablokker
12 x C aliphat: +6.0
O
OH
-0.7
-O- (hydroxyl, ether) -1.0
N (amine )
-1.0
-NO2 (aliph at.)
-0.85
-NO2 (aromat.)
-0.28
N
H
Ph:
+2.0
3 x O:
-3.0
N:
-1.0
logP
+4.0
O
ClogP (SciFinder): 2.69
KJM5230-H04
Structure  Physiochemical properties
•
•
•
•
Acid / base properties
Water solubility
Partition coefficient
Crystal structure
•
Stereochemistry
cis-trans
Diastereomers
Enantiomers
(Konformers / rotamers)
OH
OH
H
H
5-reduktase
H
H
O
O
Testosterone
A / B cis fused
A / B trans fused
H
10
10
H
H
5-Dihydrotestosterone (5DHT)
More active A-B ring trans
Cis isomer inaktive
KJM5230-H04
5
5
Biomolecules (reseptors, enzymes): Asymmetric
A
D
A
C
Drug
D
C
B
B
Biomolecular
target
Desired responce
No desired resonce
Side 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
P
P
(S)-(-)-BINAP
(R)-(+)-BINAP
X-ray contrast agent
* CO2H
Chiral C-atom
O
I
I
Chiral axis (restrict. tot.)
NH2
I
KJM5230-H04
4 stereoisomers
•Screening/Design/Serendipity/Natural products
•Lead compound
•Structure Optimisation
Refinement of lead structure:
•Determining pharmacophore
•Functional group modification
•Actual Drug
Pharmacophore:
The part of the molecule that contains the functional groups that actually binds to the reseptor
Morfin
Petidine
N
OH
O
Dextropropoxyphene
N
N
O
O
OH
O
O
KJM5230-H04
Antimycobacterials
Ar
Lead compound
O
Z
N
N
Cl
Y
N
N
X
N
Rel high activity
N
N
N
O
R
N
N
N
N
N
N
N
N
R
R ° CH2Ph
R=H, alkyl
Inactive
Pharmacophore??
Ar
Azapurines??
N
N
Deazapurines??
N
N
Ar
Ar
Ar
N
N
N
??
KJM5230-H04
N
R
X
N
??
??
Improvement of lead by functional group modification
•Activity
•Toxicity
•Bioavailability
•Metabolism
Isosters:
Functional groups that results in approx. the same properties
Steric and electronic similarities
N
S
bp 81
oC
bp 84
bp 116 oC
oC
-CH=CH- and -S- are isosters
-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 bioisosters
Steric and electronic similarities
Tetravalente
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=
N
Rings
N
KJM5230-H04
C
S
O
-X

p
-H
-F
-OH
-NH2
-CH3
Bioisosters
0
0.15
-0.61
-1.23
0.60
0
0.06
-0.37
-0.66
-0.17
O
N
N
N
N
X
% Inhib at
6.25 g/mL
>90
>90
79
23
>90
MIC
(g/mL)
3.13
6.25
n.d.
n.d.
3.13
: electronic effects; >0 electron w it hdrawing, <0 electron dona ting
: Lipophili city, >0 incr eased li pophil . rel t o H
Angiotensin II antagonists
(Hypertention)
Non-classical bioisosters
Not strong steric or electronic similarities
O
N
N
N
N
N
N
H
pKa 14.2
N
N
H
N
pKa 10.3
N
H
N
N
pKa 9.2
N
NH
N N
N
N
H
HO2C
N
N
pKa 4.9 - karboksylsyrer
O
HO
N
KJM5230-H04
N