U inkovine za zdravljenje

hiperlipoproteinemij

Ateroskleroti ni plak

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 U inkovine za zdravljenje
hiperlipoproteinemij
• inhibitorji HMG CoA reduktaze • nikotinska kislina in derivati
LOVASTATIN NIKOTINSKA KISLINA
SIMVASTATIN NIKOTINIL ALKOHOL
PRAVASTATIN ACIPIMOKS
ATORVASTATIN nižajo nivo VLDL v plazmi
FLUVASTATIN • drugi zaviralci sinteze holesterola
CERIVASTATIN DEKSTROTIROKSIN
• zavirajo biosintezo holesterola PROBUKOL
• ariloksikarboksilne kisline (fibrati) nižajo nivo LDL in HDL v plazmi
KLOFIBRAT • adsorbenti žol nih kislin Pove ajo
FENOFIBRAT HOLESTIRAMIN pretvorbo
ETOFIBRAT HOLESTIPOL holesterola
BEZAFIBRAT v žol ne ksl
GEMFIBROZIL • zaviralci lipaze
ORLISTAT
nižajo nivo VLDL v plazmi

Holesterol
H3C

CH3
H CH3
CH3
H3C

H H

HO

2
Shematski model LDL
(2r = 22 nm)

Biosinteza holesterola
acetil koencim A

3-hidroksi-3-metilglutaril-koencim A
(HMG-CoA)
HMG-CoA
reduktaza

L-mevalonska kislina

skvalen
sintetaza

skvalen

skvalen
poksidaza
lanosterol

lanosterol 14-alfa
demetilaza
holesterol

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Encimska redukcija HMG-CoA v mevalonsko kislino

CH3 HMG-CoA -
HO reduktaza CH3
COOH
HO
COOH
O
OH
SCoA
mevalonska
HMG-CoA kislina

H H
HO O HO
COOH
Karl Folkers
O OH
Carl Hoffmann

R R Merck, 1956
mevastatin (kompaktin) aktivni metabolit
lovastatin
simvastatin

Naravni inhibitorji
HMG-CoA reduktaze
HO O HO O

O O
O O

H3C O H3C O
CH3 H CH3 H
CH3 CH3

H3C

mevastatin (iz P. citrinum) lovastatin (iz Aspergillus terreus

Sankyo (1976) Merck (1979)

kompaktin (iz P. brevicompactum)

Beecham (1977)
FDA registracija 1987

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 Pravastatin in simvastatin
HO O
lakton HO O

O O
O O

H3C O H3C O
CH3 H CH3 H
CH3 CH3

H3C

mevastatin
heksahidro- lovastatin
naftalen
Nocardia polsinteza
autotrophica

β,δ-dikarboksilna (di)metilbutirat
kislina HO
COO Na
- +
HO O

OH O
O
O
H3C O
H3C O H3C CH3 H
CH3 H CH3
CH3

H3C
HO

pravastatin simvastatin

Tipi inhibitorjev HMG-CoA reduktaze

predzdravila HO

O
O HO

O
O HO

O
O

O O O

H3C O H3C O H3C O

CH3 H CH3 H H3C CH3 H
CH3 CH3 CH3

H3C H3C

mevastatin (kompaktin) lovastatin simvastatin

aktivne HO
COO Na
- + HO
COO Na
- + HO
COO Na
- +

OH OH OH

u inkovine O
CH3
H3C O F CH3
CH3 H
CH3 N CH3
CH3
O N
H3C
HO
H3C CH3

pravastatin fluvastatin cerivastatin

5
 Lipofilnost
inhibitorjev HMG-CoA reduktaze
100 000 100 1
H3C

CH3 CH3 H3C

H H
H3C O

H CH3 CH3
O H H
HO
O H3C O

H
HO O O CH3 CH3
OH H H
O
H3C O
HO OH H
O
OH
O

HO OH

lovastatin lovastatinska kislina pravastatin

Lipofilnost
inhibitorjev HMG-CoA reduktaze

U inkovina log P* log P

pravastatin 0.51
lovastatin 3.11
fluvastatin 3.24
atorvastatin 4.06 hepatoselektivnost
___________
*izra unane vrednosti

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 Registrirani inhibitorji HMG-CoA reduktaze

HO O HO O HO - +
COO Na
O O OH
O O O

H3C O H3C O H3C O

CH3 H H3C CH3 H H
CH3 CH3 CH3 CH3

H3C H3C HO
7 C veriga
lovastatin (Merck, 1987) simvastatin (Merck, 1988) pravastatin (Bristol-Myers Squibb, 1989)

HO - 2+
COO Ca
OH
HO - +
HO - + COO Na
COO Na
OH CH3
OH F

N
CH3 CH3
F CH3
CH3 O
N HN
CH3 O N
H3C

H3C CH3

fluvastatin (Novartis, 1994) cerivastatin (Bayer, 1997) atorvastatin (Parke-Davis, Warner-Lambert, 1997)

Rosuvastatin (CRESTOR)

! "
! # "
$
#
# $

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 Superpozicija
inhibitorjev HMG-CoA reduktaze

lovastatin fluvastatin

Prikaz elektrostatskega potenciala

inhibitorjev HMG-CoA reduktaze

lovastatin fluvastatin
podro je negativnega naboja
podro je pozitivnega naboja

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 Sinteza pravastatina

Sinteza simvastatina (1/2)

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 Sinteza simvastatina (2/2)

Registrirani inhibitorji HMG-CoA reduktaze

HO O HO O HO - +
COO Na
O O OH
O O O

H3C O H3C O H3C O

CH3 H H3C CH3 H H
CH3 CH3 CH3 CH3

H3C H3C HO

lovastatin (Merck, 1987) simvastatin (Merck, 1988) pravastatin (Bristol-Myers Squibb, 1989)

HO - 2+
COO Ca
OH
HO - +
HO - + COO Na
COO Na
OH CH3
OH F

N
CH3 CH3
F CH3
CH3 O
N HN
CH3 O N
H3C

H3C CH3

fluvastatin (Novartis, 1994) cerivastatin (Bayer, 1997) atorvastatin (Parke-Davis, Warner-Lambert, 1997)

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Sinteza atorvastatina (1/4)

Knoevenagel

umpolung

sinteza pirolov
Paal-Knorr

Sinteza atorvastatina (2/4)

* *
*
aldolna reakcija

preestrenje

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 Sinteza atorvastatina (3/4)

1. odš ita
2. laktonizacija

Registrirani inhibitorji HMG-CoA reduktaze

HO O HO O HO - +
COO Na
O O OH
O O O

H3C O H3C O H3C O

CH3 H H3C CH3 H H
CH3 CH3 CH3 CH3

H3C H3C HO

lovastatin (Merck, 1987) simvastatin (Merck, 1988) pravastatin (Bristol-Myers Squibb, 1989)

HO - 2+
COO Ca
OH
HO - +
HO - + COO Na
COO Na
OH CH3
OH F

N
CH3 CH3
F CH3
CH3 O
N HN
CH3 O N
H3C

H3C CH3

fluvastatin (Novartis, 1994) cerivastatin (Bayer, 1997) atorvastatin (Parke-Davis, Warner-Lambert, 1997)

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 Sinteza cerivastatina (1/4)

Knoevenagel

Hantzscheva
sinteza
Michaelova 1,4-dihidropiridinov
adicija

enamin

Sinteza cerivastatina (2/4)

Wittig-Horner-Emmons

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Sinteza cerivastatina (3/4)

Sinteza cerivastatina (4/4)

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 Registrirani inhibitorji HMG-CoA reduktaze

HO O HO O HO - +
COO Na
O O OH
O O O

H3C O H3C O H3C O

CH3 H H3C CH3 H H
CH3 CH3 CH3 CH3

H3C H3C HO

lovastatin (Merck, 1987) simvastatin (Merck, 1988) pravastatin (Bristol-Myers Squibb, 1989)

HO - 2+
COO Ca
OH
HO - +
HO - + COO Na
COO Na
OH CH3
OH F

N
CH3 CH3
F CH3
CH3 O
N HN
CH3 O N
H3C

H3C CH3

fluvastatin (Novartis, 1994) cerivastatin (Bayer, 1997) atorvastatin (Parke-Davis, Warner-Lambert, 1997)

Sinteza fluvastatina (1/3)

Fischerjeva
sinteza
indolov

Analogija z
Wittigovo
reakcijo

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Sinteza fluvastatina (2/3)

* *

Sinteza fluvastatina (3/3)

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 U inkovine za zdravljenje
hiperlipoproteinemij
• inhibitorji HMG CoA reduktaze • nikotinska kislina in derivati
LOVASTATIN NIKOTINSKA KISLINA
SIMVASTATIN NIKOTINIL ALKOHOL
PRAVASTATIN ACIPIMOKS
ATORVASTATIN
FLUVASTATIN • drugi zaviralci sinteze holesterola
CERIVASTATIN DEKSTROTIROKSIN
PROBUKOL
• ariloksikarboksilne kisline (fibrati)
KLOFIBRAT • adsorbenti žol nih kislin
FENOFIBRAT HOLESTIRAMIN
ETOFIBRAT HOLESTIPOL
BEZAFIBRAT
GEMFIBROZIL • zaviralci lipaze
ORLISTAT
nižajo nivo VLDL v plazmi

Sinteza fenofibrata

Friedl-Crafts

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 U inkovine za zdravljenje
hiperlipoproteinemij
• inhibitorji HMG CoA reduktaze • nikotinska kislina in derivati
LOVASTATIN NIKOTINSKA KISLINA
SIMVASTATIN NIKOTINIL ALKOHOL
PRAVASTATIN ACIPIMOKS
ATORVASTATIN nižajo nivo VLDL v plazmi
FLUVASTATIN • drugi zaviralci sinteze holesterola
CERIVASTATIN DEKSTROTIROKSIN
PROBUKOL
• ariloksikarboksilne kisline (fibrati)
KLOFIBRAT • adsorbenti žol nih kislin
FENOFIBRAT HOLESTIRAMIN
ETOFIBRAT HOLESTIPOL
BEZAFIBRAT
GEMFIBROZIL • zaviralci lipaze
ORLISTAT

Sinteza acipimoksa

Polonovsky !

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 Sinteza probukola

Zaviralci apetita z vnanjim delovanjem

orlistat (1998)
(zavira lipazo v GIT)
Orlistat is the partially hydrated form of a naturally occurring molecule called lipstatin.

It is a potent, specific and long acting inhibitor of gastric and pancreatic lipases.

It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond

with the active serine site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable

to hydrolyse dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides.

As undigested triglycerides are not absorbed, the resulting loss of calories has a positive effect on weight control.

Systemic absorption of the drug is minimal and is not needed for activity.

Any metabolism seems (based on animal studies) to occur in the gastrointestinal wall.

Elimination of the unabsorbed drug is via faecal excretion (less than 2% is excreted renally).

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 Sinteza orlistata
Ekvivalent t-BuOAc

laktonizacija

Nato odš ita (cepitev tetrahidropiranilnega etra s p-TsOH

nakar sledi estreneje z zaš iteno amin okislino

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