Zaviralci angiotenzinske

konvertaze (ACE)

Antagonisti receptorjev
angiotenzina II

D. Kikelj

Sistem renin - angiotenzin

angiotenzinogen
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu- Val-Ile-His-Protein

renin ditekeren, enalkiren

remikiren, zankiren
angiotenzin I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe- His-Leu

angiotenzin konvertaza (ACE)

angiotenzin I kimaza

angiotenzin II
Asp -Arg-Val-Tyr-Ile-His-Pro-Phe Stimulira izlo anje aldosterona !!!

aminopeptidaze

angiotenzin III neaktivni

Arg-Val-Tyr-Ile-His-Pro-Phe peptidni fragmenti
angiotenzinaze

1
 Angiotenzin konvertaza

angiotenzin I

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

angiotenzin konvertaza (ACE)

angiotenzin II

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

Bothrops jararaca

Ferreira, 1965

2
 Spojina Ki/ IC50

Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro teproid Ki = 100 nM

CH3
N
H2N Ki = 230 µM
O
COOH

N
HOOC IC50 = 70 µM
O
COOH

CH3
N
HOOC IC50 = 4.9 µM
O COOH

CH3
HS N kaptopril IC50 = 23 nM
O COOH Ki = 1.7 nM

ACE - membranski glikoprotein M = 1.3-1.6 kDa

sekvenca dolo ena 1988

Ondetti, Cushman: hipoteza, da je ACE strukturno podobna

karboksipeptidazi A (metaloproteaza),
za katero je bila znana kristalna struktura
(Lipscomb) in inhibitor (benziljantarjeva
kislina)

3
 Struktura kompleksa
karboksipeptidaza A - benziljantarjeva kislina

Karboksipeptidaza A

v v
lipofilni zep lipofilni zep

Zn2+ Zn2+

O O
H O
N O +
N + HO NH2
H NH2
R O O
H2N N H2N N
H H

substrat inhibitor (benziljantarjeva kislina)

Lipscomb

4
 Inhibitorji ACE

2
O R O
H
N
N OH substrat
3 H R
1
R O

2
O R O
H
N inhibitor
HO OH
1
O R

Razvoj kaproprila (1980)

Spojina Ki/ IC50

Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro teproid Ki = 100 nM

CH3
N
H2N Ki = 230 µM
O COOH

N
HOOC
IC50 = 70 µM
O COOH

CH3
N
HOOC
IC50 = 4.9 µM
O COOH

CH3
HS N kaptopril IC50 = 23 nM
O COOH Ki = 1.7 nM Ondetti
(Squibb)

5
 Enalapril - predzdravilo (1984)

CH3 biotransformacija CH3

EtOOC N N
N HOOC N
H O H O
COOH COOH

enalapril
IC50 = 1 nm
enalaprilat
Ki = 0.2 nM

N
O O
N
CH3 H3C COOEt
EtOOC N
N
H O COOEt

Registrirani inhibitorji ACE

NH2
CH3 CH3 H3C
HS N CH3 H3C S N CH3
O ROOC N O EtOOC N
COOH N N O COOH N
H O HOOC N O N H O
COOH H O H COOH
COOH
kaptopril R = C2H5: enalapril (Merck, 1984)
(1980, Bristol-Myers Squibb) R = H: enalaprilat (Merck, 1987) lizinopril (1987, Merck) alacepril (1988, Dainippon) perindopril (Daiichi, 1988)

S n
CH3 S N
CH3
CH3 N N N
EtOOC N EtOOC EtOOC N EtOOC N N
N N H COOH
EtOOC N H O COOH H O O COOH H O
H O COOH
COOH

n = 1: ramipril (HMR, 1989)

delapril (Takeda, 1989) spirapril (Novartis, 1995) n = 2: trandolapril (HMR, 1993) cilazapril (Roche, 1990) benazepril (Novartis, 1990)

R
R
O CH3 S
CH3 N S CH3
EtCOO O N EtOOC N EtOOC N
P N EtOOC N N N
O H O COOH H O COOH
O COOH COOH H O
H3C CH 3
fosinopril (Bristol-Myers Squibb, 1991) imidapril (Tanabe, 1993) temokapril (Sankyo, 1994) R = H: quinapril (Parke-Davis, 1989)
R = OMe: moexipril (Warner-Lambert, 1995)

6
 Tipi inhibitorjev ACE
NH2

CH3
HS N CH3

ROOC N
O COOH N N
H HOOC N
O COOH H
O COOH

kaptopril enalapril lizinopril

CH3 CH3
EtCOO O N ROOC N ROOC N
P N N
H H
O O COOH O COOH O COOH
H3C CH3

fosinopril

CH3
ROOC N
N
H O COOH

enalapril

H3C n
CH3 CH3 N
N N N
EtOOC N EtOOC N EtOOC N
H O H O H
COOH COOH O COOH

n = 1: ramipril
perindopril n = 2: trandolapril cilazapril

R
R

CH3 CH3
EtOOC N N
EtOOC N N COOH
N EtOOC N H
H O H O
COOH O COOH

R = H: quinapril
R = OMe: moexipril delapril benazepril

CH3 S S
O
N S S
CH3 CH3
EtOOC N EtOOC N
N N N
H O H O EtOOC N
COOH COOH H COOH
O

imidapril spirapril temokapril

7
Kombinatorna kemija...
CH3
HS N

O
COOH

kaptopril (Ki = 1.7 nm)

COOCH3

CH3
HS N

O COOH Affymax

(Ki = 160 pm)

Sinteza kaptoprila

8
 Sinteza enalaprilata in enalaprila

PhCH2CH2MgBr

(COOEt)2

EDC/HOBt metoda tvorbe peptidne vezi

9
Sinteza lizinoprila

Sinteza perindoprila
Me(CH2)2COCOOEt L-Ala

10
 Sinteza perindoprila
1. Redukcija
O
2.
Fischerjeva sinteza indolov
H3C COOEt

Dobljen z reduktivnim aminiranjem

Sinteza
fozinoprila

11
Sinteza
fozinoprila

Sinteza fozinoprila

12
Sinteza
fozinoprila

tioketal
aktivni ester
N-hidroksi-
sukcinimida

Reduktivno
aminiranje Sinteza
spiraprila

13
Sinteza
Dualni inhibitor
omapatrilata ACE in neutralne
endopeptidaze

Inhibitor
neutralne Swernova
oksidacija
endopeptidaze,

ki razgrajuje ANP
s hipotenzivnimi
lastnostmi

14
 !

Zaviralci angiotenzinske
konvertaze (ACE)

Antagonisti receptorjev
angiotenzina II

D. Kikelj

15
 Sistem renin - angiotenzin
angiotenzinogen
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu- Val-Ile-His-Protein

renin

antagonisti
angiotenzin I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe- His-Leu

angiotenzin konvertaza (ACE)

angiotenzin I kimaza

angiotenzin II vezava na
Asp -Arg-Val-Tyr-Ile-His-Pro-Phe AT receptorje

aminopeptidaze

angiotenzin III neaktivni

Arg-Val-Tyr-Ile-His-Pro-Phe peptidni fragmenti
angiotenzinaze

Razvoj losartana
Cl
saralazin N - Takeda, S-8308
COO
Sar-Arg-Val-Tyr-Val-His-Pro-Ala
N spojina vodnica

kisle skupine

NO2
1982

+
H2N NH2
HO H
HN N

N
O O O
H H
H2N N N N
N N N
H H H -
O O O COO
- N
OOC O H

angiotenzin

16
 Razvoj losartana
Cl
Cl Cl N
N - N -
COOEt
COO COO
N
N N
O

N
NO2 COOH H
HOOC
S-8308
IC50 = 15 µ M IC50 = 1.2 µ M IC50 = 0.12 µM

Cl
N Cl
OH N
OH
N
N

N
N HOOC
N NH
IC50 = 0.019 µ M IC50 = 0.23 µ M

losartan peroralno uporabna!

Antagonisti angiotenzina II
Cl CH3 H3C CH3 CH3
N O CH3
HO HO S CH3
N
N N N N N N N
- +
O HOOC O N N N
N NK N NH
N N NH

COOH

eprosartan irbesartan
losartan (Merck, Banyu, 1994) valsartan (Novartis, 1996) (SmithKline Beecham, 1997) (Bristol-Myers Squibb, 1997)

CH3 Cl CH3 CH3

CH3 OH
O CH3 CH3 N O H3C
N N N O
CH3 CH3
HOOC N
O O N N N N N O O
O N N N
O N NH N NH N N N
O CH3
COOH O N NH

telmisartan
candesartan cileksetil (Takeda, 1997) (Boehringer Ingelheim, 1999) EXP-3174 (faza III) CS-866 (Sankyo, faza III)

17
Sinteza losartana

Sinteza losartana

18
 Sinteza losartana

N N
N N
N N
N N H3C N N
BrCH2 Tr
BrCH2 N N Tr
Tr

Ullmannova reakcija

Sinteza losartana

19
Sinteza
valsartana

Sinteza
valsartana

20
 Sinteza irbesartana

O H2N CN 1. H2SO4 H3C

1. NaCN
2. NH3 2. C4H9-COCl H
N
N
O

Br

, NaH
O N O
N CN
N N

H3C NaN3 H3C

N N
N NC
N
H

irbesartan

Sinteza kandesartana
COOH COOMe COOMe
1. MeO H, H+ 1. NaN3
COOH C O Cl 2 . t-B u O H N H C O O -t- B u
2 . S O C l2

NO2 NO2 Schmittova NO2

reakcija Br

, NaH
1 . S n C l2 COOMe
2 . e tilo r to k a rb o n a t CN
N
H NC

NO2

1. N aN 3
COOMe 2 . N a O H , H 2O COOH
3. T rC l
N N
NC N
O Et O Et
N N N Tr
N N

O O I
, N aO H
O O O O O Me

O C H3 N
N
O Et
N N N Tr
N

k a n d e s a r ta n c ile k s e til

21