Bioisosteres: a Useful Concept in Medicinal Chemistry · 2018. 10. 23. · F Haloperidol D2 D3 1.3 nM 7.3 nM 10 nM D4 D C H HO Cl O F carba - Haloperidol D2 D3 50 000 nM 47 000 nM

EMIL FISCHER CENTRUM UNIVERSITÄT ERLANGEN

Bioisosteres: a Useful Concept in Medicinal Chemistry

Peter Gmeiner, Rio de Janeiro 2009


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


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)

4 portraits of cats of the Londoner painter

Louis Wain(early 20th century)

= proceeding of the psychosis

Classical antipsychotics show extrapyramidal motoric side effects(similar to Parkinson`s disease) in rats: catalepsy

Dopaminergic synapse

Signal transduction (simplified):

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


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aminophenazone (carcinogenic properties, withdrawn 1978)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:



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



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




Pyrrole

D2 14

D3 49

D4 4

Pyrazole

D2 470

D3 120

D4 0.45

N

NPhpip

N N

NPhpip


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:


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

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

Fancy bioisosteres: fullerene-based HIV inhibitors

G. Kenyon , JACS 1993, 6506


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


X X

NPr2NH2

OHOH

OH

NR2 NHPr

NS

NH2

NPr2

X

dopamine

pramipexole

Fancy bioisosteres: non-aromatic arene surrogates


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


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


NH2

OHOH

OH

NPr2 NHPr

NS

NH2

NPr2 NPr2

X

NPr2

Dopamine

7-HO-DPAT Pramipexole

FAUC 73



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


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



-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

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


Fancy bioisosteres: bilayered arene surrogates

1. Paracyclophanes


NN

NN

π1

π1

π2

NN

π2

π1

π2

π1

π2

Fancy bioisosteres: paracyclophanes as bilayered arene surrogates

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)


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


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)

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


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

Fancy bioisosteres

GPCR PLASTICITY

Documents

Bioisosteres: a Useful Concept in Medicinal Chemistry · 2018. 10. 23. · F Haloperidol D2 D3 1.3 nM 7.3 nM 10 nM D4 D C H HO Cl O F carba - Haloperidol D2 D3 50 000 nM 47 000 nM