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
ditekeren, enalkiren remikiren, zankiren
renin 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 neaktivni peptidni fragmenti
angiotenzin III Arg-Val-Tyr-Ile-His-Pro-Phe 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 Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro
Ki/ IC50 teproid
Ki = 100 nM
CH3 H2N
N O
Ki = 230 µM
COOH
N
HOOC O
IC50 = 70 µM
COOH
CH3 N
HOOC O
IC50 = 4.9 µM
COOH
CH3 HS
N O
kaptopril COOH
ACE - membranski glikoprotein
IC50 = 23 nM Ki = 1.7 nM
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
H N R
O N H
O +
NH2
O H2N
substrat
N H
O
HO O
H2N
+
NH2
N H
inhibitor (benziljantarjeva kislina)
Lipscomb
4
Inhibitorji ACE O R
R
2
N H
3
O
R
O
R
O
H N
2
1
O
substrat
OH
inhibitor
O
H N
HO
OH
R
1
Razvoj kaproprila (1980) Spojina Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro
Ki/ IC50 teproid
Ki = 100 nM
CH3 H2N
N O
Ki = 230 µM
COOH
N
HOOC O
IC50 = 70 µM
COOH
CH3 N
HOOC O
IC50 = 4.9 µM
COOH
CH3 HS
N O
kaptopril COOH
IC50 = 23 nM Ki = 1.7 nM
Ondetti (Squibb)
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Enalapril - predzdravilo (1984) biotransformacija
CH3 EtOOC
N H
CH3
N
HOOC
O
N H
COOH
IC50 = 1 nm Ki = 0.2 nM
enalapril
N
O
COOH
enalaprilat
N O CH3 EtOOC
N H
O N
H3C
N
O
COOEt
COOEt
Registrirani inhibitorji ACE NH2 CH3
HS
CH3
N
O
COOH
kaptopril (1980, Bristol-Myers Squibb)
ROOC
N H
O
H3C
N COOH
R = C2H5: enalapril (Merck, 1984) R = H: enalaprilat (Merck, 1987)
S CH3 EtOOC
N H
CH3 EtOOC
N
O
COOH
delapril (Takeda, 1989)
N H
O
HOOC
N H
COOH
spirapril (Novartis, 1995)
H3C
N
O
COOH
lizinopril (1987, Merck)
N H
O
CH3 EtOOC
N H
N
O
EtOOC COOH
n = 1: ramipril (HMR, 1989) n = 2: trandolapril (HMR, 1993)
N H
COOH
N H
EtOOC
COOH
cilazapril (Roche, 1990)
EtCOO H3C
O P O CH 3
N O
EtOOC COOH
fosinopril (Bristol-Myers Squibb, 1991)
imidapril (Tanabe, 1993)
EtOOC
N H
N O
COOH
temokapril (Sankyo, 1994)
CH3 EtOOC
O
COOH
benazepril (Novartis, 1990)
S
S
COOH
N
N H
R CH3 O N CH3 N N H O COOH
N
O
perindopril (Daiichi, 1988)
N N O
CH3
EtOOC
alacepril (1988, Dainippon)
n
S
N
CH3
O
N O
S
N H
O
R
N COOH
R = H: quinapril (Parke-Davis, 1989) R = OMe: moexipril (Warner-Lambert, 1995)
6
Tipi inhibitorjev ACE NH2 HS
CH3
CH3
N ROOC
COOH
O
kaptopril
N
N H
COOH
O
HOOC
N
N H
enalapril
lizinopril
CH3 EtCOO H3C
O
N
P
O CH3
ROOC
CH3 N
N H
COOH
O
COOH
O
ROOC COOH
O
N
N H
O
COOH
fosinopril
CH3 ROOC
N H
N
O
COOH
enalapril H3C
n CH3
EtOOC
N H
CH3
N
EtOOC
O
COOH
R
CH3 N H
CH3
N
O
O CH3 N H
O
imidapril
O
EtOOC COOH
N N
N H
O
COOH
cilazapril
R
EtOOC COOH
R = H: quinapril R = OMe: moexipril
EtOOC
N
n = 1: ramipril n = 2: trandolapril
perindopril
EtOOC
N H
N H
EtOOC
N
O
COOH
S
CH3 N
CH3 EtOOC
COOH
N
N H
COOH
O
benazepril
delapril
N
N H
O
spirapril
S
S N COOH
S EtOOC
N H
N O
COOH
temokapril
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Kombinatorna kemija... CH3 HS
N O
COOH
kaptopril (Ki = 1.7 nm)
COOCH3 HS
CH3 O
N 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 2. H3C
O COOEt
Fischerjeva sinteza indolov
Dobljen z reduktivnim aminiranjem
Sinteza fozinoprila
11
Sinteza fozinoprila
Sinteza fozinoprila
12
Sinteza fozinoprila
tioketal
Reduktivno aminiranje
aktivni ester N-hidroksisukcinimida
Sinteza spiraprila
13
Sinteza omapatrilata Inhibitor neutralne endopeptidaze,
Dualni inhibitor ACE in neutralne endopeptidaze Swernova oksidacija
ki razgrajuje ANP s hipotenzivnimi lastnostmi
14
!
Natesh R et al. Nature 2003, 551
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
vezava na AT receptorje
angiotenzin II Asp -Arg-Val-Tyr-Ile-His-Pro-Phe aminopeptidaze
neaktivni peptidni fragmenti
angiotenzin III Arg-Val-Tyr-Ile-His-Pro-Phe angiotenzinaze
Razvoj losartana Cl
saralazin Sar-Arg-Val-Tyr-Val-His-Pro-Ala
N
COO
Takeda, S-8308
-
N
spojina vodnica
kisle skupine
1982
NO2
+
H2N
NH2
HO
H N
HN O H2N -
OOC
N H
H N O
O N H
H N O
N
O N H
N O
O
N H
COO
-
angiotenzin
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Razvoj losartana Cl
Cl
Cl
N
COO
N
N
-
N
COO
-
COOEt N
N
O NO2
N H
COOH
HOOC
S-8308 IC50 = 15 µ M
IC50 = 1.2 µ M
IC50 = 0.12 µM
Cl N
Cl N
OH N
OH N
N
N HOOC
N NH IC50 = 0.019 µ M
IC50 = 0.23 µ M
losartan
peroralno uporabna!
Antagonisti angiotenzina II Cl HO
CH3
H3C
N
HO
N N - + NK N
N
O
CH3 O
CH3
CH3
CH3
S
N
N
N N NH N
N
HOOC
O
N N N NH
N
N
COOH
losartan (Merck, Banyu, 1994)
valsartan (Novartis, 1996)
eprosartan (SmithKline Beecham, 1997)
CH3 O O
O
O
CH3
N
CH3
N O
O
N N NH N
candesartan cileksetil (Takeda, 1997)
N N CH3
Cl N
CH3 HOOC
N
CH3 N N
O N N NH N
O
CH3 H3C
O
O O
COOH
telmisartan (Boehringer Ingelheim, 1999)
irbesartan (Bristol-Myers Squibb, 1997)
EXP-3174 (faza III)
CH3
OH N
N
CH3 N N N NH
CS-866 (Sankyo, faza III)
17
Sinteza losartana
Sinteza losartana
18
Sinteza losartana
BrCH2 BrCH2
N N N N N N N N Tr Tr
N N H3C
N
N
Tr
Ullmannova reakcija
Sinteza losartana
19
Swernova oksidacija
Sinteza valsartana
reduktivno aminiranje
Sinteza valsartana
20
Sinteza irbesartana O
H2N
1. NaCN 2. NH3
H3C
1. H2SO4 2. C4H9-COCl
CN
H N N
O
Br
, NaH O
N
O
N
NaN3
H3C
N
CN
N
N H3C
N N
NC
N H
irbesartan
Sinteza kandesartana COOH
COOMe
1. MeO H, H+ 2 . S O C l2
COOH
C O Cl
N H C O O -t- B u
Schmittova reakcija
NO2
NO2
COOMe
1. NaN3 2 . t-B u O H
NO2 Br
, NaH 1 . S n C l2 2 . e tilo r to k a rb o n a t
COOMe CN
N H
NC
NO2 1. N aN 3 2 . N a O H , H 2O 3. T rC l
COOMe N
N
NC
O Et
N
COOH
N
O Et
N N
N
N O
O
O O
O C H3
O O
O N N
O Et
Tr I Me
, N aO H
N N
N
N
Tr
k a n d e s a r ta n c ile k s e til
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