bioisosteres: a useful concept in medicinal chemistry · 2018. 10. 23. · f haloperidol d2 d3 1.3...
TRANSCRIPT
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
Bioisosteres: a Useful Concept in Medicinal Chemistry
Peter Gmeiner, Rio de Janeiro 2009
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
A bioisostere is a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or groups of atoms. The objective of a bioisosteric replacement is to create a new compound presenting similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based (IUPAC, Glossary of terms used in medicinal chemistry).
Classical bioisosteres result from classical isosteres (isoelectronic compounds) = unusual restriction
What is a bioisostere?
Why to perform a bioisosteric replacement?
• Pharmacokinetics• Drug safety• Target recognition and activity• Selectivity
• Patent issues• Availability• Target – small molecule interactions
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
NOVEL DOPAMINERGICS FOR THE TREATMENT OF NEUROLOGICAL AND PSYCHIATRIC DISEASES
Schizophrenia:
abnormal thinking, feeling and perception of surroundings
positive symptoms: hallucinations, delusions, hyperactivity,abnormal use of language
negative symptoms: apathy, limited speech, affective flattening(= blunted emotions, loss of interest)
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4 portraits of cats of the Londoner painter
Louis Wain(early 20th century)
= proceeding of the psychosis
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Classical antipsychotics show extrapyramidal motoric side effects(similar to Parkinson`s disease) in rats: catalepsy
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Dopaminergic synapse
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Signal transduction (simplified):
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Effector functionconsidering as example the phosphatidylinositol specific phospholipase C (PI-PLC):
H
H
OH
HH
OH
H
HOOPO3
HOPO3
O3PO2-
2-
2-
--
-
-
-
CO
O
H2C
H
H
OH
HH
OH
H
HOO
HO
O
C OOCH CH2
OP OO
PO
O O
P OO
O
CO
O
H2C
C OOCH CH2OH
protein kinase C ↑
Ca2+IP3
ER
receptor(Ca2+-channel)
phosphatidylinositol diphosphate (PIP2)
diacylglycerol(DAG)
inositoltriphosphate (IP3)
( inositol: meso form )
IP3 + DAG:second messenger
PI-PLC
M M M Mphosphatidylinositol: phospholipid(part of the membrane)
HO
OH
OHOH
HOHO
plane of symmetry σ
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
Displacement of atoms or pseudo-atoms
Bioisosterism involving O, N(H), CH(2),S and halogens:
NN
N CH3
CH3O
Ph
CH3CH3 NH
CH3CH3 N N O
CH3
CH3
OH
+
NN
CH CH3
CH3O
Ph
CH3CH3
aminophenazone (carcinogenic properties, withdrawn 1978)
dimethylnitrosamine
HNO2H2O
propyphenazone
NSAIDs:
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
Displacement of atoms or pseudo-atoms
Antipsychotics:
N
OHCl
O
F Haloperidol
D2D3
1.3 nM
7.3 nM10 nM
D4
D
CH
OHCl
O
F carba - Haloperidol
D2D3
50 000 nM
47 000 nM2 500 nM
D4
D = completely conserved Asp 3.32 central position of the binding site crevice mutation leads to complete loss of ligand binding
Bioisosterism involving O, N(H), CH(2),S and halogens:
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
0
2000
4000
6000
8000
10000
12000
FAUC 113 Indole
D1D2 longD2 shortD3D4
N N
N NCl
NH
N NCl
FAUC 113
D4 Subtype Selectivity
Displacement of atoms or pseudo-atoms
Bioisosterism involving O, N(H), CH(2),S and halogens:
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
Pyrrole
D2 14
D3 49
D4 4
Pyrazole
D2 470
D3 120
D4 0.45
N
NPhpip
N N
NPhpip
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
Sulfonamides as p-aminobenzoic acid analogs inhibitingdihydropteroate synthesis:
Displacement of functional groups
Bioisosterism of carboxylic acids and carboxamides:
NH2 CO2H NH2 SO2NH R
dipeptide
R
NH2O
N
R'
H
OH
O R
NH2OH R''
R'
OH
O
hydroxypropylene bioisostereindinavir
HIV protease inhibitors:
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
Histamine H2 receptor antagonists:
Displacement of functional groups
Bioisosterism involving arenes: (hydroxy)benzeneindoleimidazole } heteroarenes
OS
NH
NH
CH3
NO2
NH3C
CH3
N
NH
NH2 N
NH
NH
NH
SCH3
burimamidehistamine
ranitidine
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NH
N N
NN
X X
X
N NX
X Hal
O
CH 56D1 D2shortD2long D3 D4
1
10
100
1000
10000
CH 56 NGD 94-1
2,2-Dicyanovinyl substituted D4 ligands
How academia can help drug discovery ?
Riskier approaches: - tackling orphan diseases - novel types of assays - creating new animal models for disease - novel types of compounds
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Fancy bioisosteres: fullerene-based HIV inhibitors
G. Kenyon , JACS 1993, 6506
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
N N N N N N N N
N N
NN
Cl
NN
Cl
NN
MeO
+ +δ+ δ−
+
δ+ δ−
+
FAUC 113 FAUC 3019
Ki = 3.6 nM (D4) Ki = 0.38 nM (D4)Ki = 69 nM (D4)
Fancy bioisosteres: carbocyclic derivatives
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
X X
NPr2NH2
OHOH
OH
NR2 NHPr
NS
NH2
NPr2
X
dopamine
pramipexole
Fancy bioisosteres: non-aromatic arene surrogates
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
NPr2
OTf
NPr2
O
NPr2
Br BrX X
NPr2
NPr2
X
X = C-Ph, C-Si(Me)3, C-H, N
Tf2O XH
Pd(PPh3)4, CuI
XH
Cl2Pd(PPh3)2 CuI
CBr4, PPh3
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
20
270
16
250
50
5 12 21 7
500
D2long D2short D3 D4 D1
0
100
200
300
400
500
DA C73
N
H
FAUC 73
J. Med. Chem. 2000, 756
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
NH2
OHOH
OH
NPr2 NHPr
NS
NH2
NPr2 NPr2
X
NPr2
Dopamine
7-HO-DPAT Pramipexole
FAUC 73
Fancy bioisosteres: non-aromatic arene surrogates
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
NPr2
OTfBr
NPr2
O
NPr2
Br
SiMe3
XH
H SiMe3
NPr2
OBr
NPr2
OTfBr
N NTf2
Cl
NPr2
H
X
NPr2
H
H 2. Bu4NF
Pd(PPh3)4 CuI, Piperidin, 40°C
LDA, (Cl2BrC)2+
LiN(SiMe3)2
Pd(PPh3)4 CuI, Piperidinreflux
1.
1. Tf2O2. H2C=CHSnBu3
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
20 17
50
1
270250
522
94
54
3 6
230
100
6
260
DA FAUC 73 FAUC 88 FAUC 206
0
50
100
150
200
250
300
D2long D2shortD3 D4
NH2
OHOH
NPr2
H
NPr2
H
H
NPr2
H
H
Dopamine FAUC 73
FAUC 206FAUC 88
Fancy bioisosteres: non-aromatic arene surrogates
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
-12 -11 -10 -9 -8 -7 -6 -5
0
25
50
75
100FAUC 88 (EC50 = 2.5 nM)quinpirole (EC50 = 2.7 nM)
log test compound [M]
[³H]T
hym
idin
e-in
corp
orat
ion
[%]
NPr2
H
H
FAUC 88
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D3 and D4 Antagonists
for D3: n = 3
Elongation of the distance between N and π1 generates D3 selectivity !
NX
π2
π1( ) n
NH
NN
Cl
N N
NN
Cl
MSD
D2D3
810 nM
1.0 nM430 nM
D4
D2D3
4700 nM
2.0 nM5000 nM
D4
FAUC 113
Shortening of the distance between N and π1 generates D4 selectivity !
for D4: n = 0
N
O
H
NN
O
SN
O
H
NN
ClCl
BP 897
D2D3
210 nM
39 nM1.4 nM
D4
D2D3
3600 nM
340 nM0.50 nM
D4FAUC 365
N
OHCl
O
F Haloperidol
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
Fancy bioisosteres: bilayered arene surrogates
1. Paracyclophanes
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
NN
NN
π1
π1
π2
NN
π2
π1
π2
π1
π2
Fancy bioisosteres: paracyclophanes as bilayered arene surrogates
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CHO NN
NHN
BrNNH N
N
NNH
NN
NN
NN
COOEt
R
NN
NaBH3CN
Ki = 75 nM (D4)
Toluol135°C
Ki = 5400 nM (D4)
1. ClCOOEt2. HCl
t-BuOK
LiAlH4
Ki = 120 nM (D4)
Ki = 250 nM (D4)
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
OO
OEt
NH
O
OEt
X NN
H
Ph
Ph
NNH2
PhPh
NH
N
N
Cl
NN
CH(OEt)2
CH(OEt)2
N
N
NN
X = Br[Pd2(dba)3]P(t Bu)3+NaOt BuToluol(87 %)
TosOHEtOH / H2O
X = OTfpure enantiomers
HCl
POCl3 / DMF
Bilayered heterocyclic systems
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
NN
NH
Cl
NN
NH
Cl
NN
NNN
N
NN
D1 1300D2l 370D2s 340D3 100 D4 12
D1 1700D2l 350D2s 240D3 23 D4 4.5
D1 1400D2l 55D2s 33D3 20 D4 2.5
D1 5500D2l 2500D2s 1400D3 270 D4 23
(R) (S)
(R) (S)
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D3 Selective Ligands
N
O
H
NN
O
SN
O
H
NN
ClCl
RN
O
H
NN
BP 897
D2D3
210 nM
39 nM1.4 nM
D4
D2D3
3600 nM
340 nM0.50 nM
D4FAUC 365
D2D3
18 (34) nM
5.4 (9.5) nM0.20 (4.1) nM
D4
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EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN
O
NH
NN
R1
R2
Me
NN
S O
NH R1
R2
NN
N
NCl
Me
N
N
R
bioisosteric replacement
D2D3
31 nM
0.63 nM0.64 nM
D4
Me = Fe; R1, R2 = Cl
D2D3
290 nM
23 nM6.0 nM
D4
Me = Fe; R = 2-OMe
Fancy bioisosteres: metallocenes as bilayered arene surrogates
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Fancy bioisosteres
GPCR PLASTICITY