Učinkovine za zdravljenje

hiperlipoproteinemij

Aterosklerotični plak

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 Učinkovine 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 žolčnih kislin Povečajo
FENOFIBRAT HOLESTIRAMIN pretvorbo
ETOFIBRAT HOLESTIPOL holesterola
BEZAFIBRAT v žolčne ksl
GEMFIBROZIL • zaviralci lipaze
ORLISTAT
nižajo nivo VLDL v plazmi

Holesterol
H3C

CH3
H CH3
CH3
H3C

H H

HO

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

1974 Testni sistemi za inhibicijo biosinteze holesterola (Merck)

1975 Rešetanje ekstraktov 8000 mikroorganizmov na biosintezo holesterola (Sankyo)

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
mevastatin (kompaktin) aktivni metabolit Merck, 1956
lovastatin
simvastatin

1974 Testni sistemi za inhibicijo biosinteze holesterola (Merck)

1975 Rešetanje ekstraktov 8000 mikroorganizmov na biosintezo holesterola (Sankyo)

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 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

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-dihidroksikarboksilna (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

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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

učinkovine O
CH3
H3C O F CH3
CH3 H
CH3 N CH3
CH3
O N
H3C
HO
H3C CH3

pravastatin fluvastatin cerivastatin

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

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 Lipofilnost
inhibitorjev HMG-CoA reduktaze

Učinkovina log P* log P

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

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)

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Rosuvastatin (CRESTOR)

Rosuvastatin calcium. a | The molecule contains the characteristic statin pharmacophore,

a dihydroxy heptenoic acid moiety that binds to the active site of 3-hydroxy-3-methylglutaryl
CoA (HMG-CoA) reductase (the structures of the substrate and product of the reaction
catalysed by HMG-CoA reductase are shown in b for comparison). The remainder of the
molecule, which is structurally distinct from the corresponding portions of other statins,
contains a polar sulphonyl moiety that confers relatively low lipophilicity.

Superpozicija
inhibitorjev HMG-CoA reduktaze

lovastatin fluvastatin

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Prikaz elektrostatskega potenciala
inhibitorjev HMG-CoA reduktaze

lovastatin fluvastatin
področje negativnega naboja
področje pozitivnega naboja

Sinteza pravastatina

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Sinteza simvastatina (1/2)

Sinteza simvastatina (2/2)

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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 atorvastatina (1/4)

Knoevenagel

Umpolung
Stetterjeva reakcija

sinteza pirolov
Paal-Knorr

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 Stetterjeva reakcija

The Stetter Reaction is a 1,4-addition (conjugate

addition) of an aldehyde to an a,β-unsaturated
compound, catalyzed by cyanide or a thiazolium
salt.

The cyanide ion effects an umpolung of the normal

carbonyl charge affinity, and the electrophilic
aldehyde carbon becomes nucleophilic after
deprotonation:

The thiazolium salts may be converted into ylides

by deprotonation. These ylides are comparable to
the cyanide adducts in their ability to catalyze the
Stetter Reaction effectively

Stetterjeva reakcija

The thiazolium salts may be converted into ylides by deprotonation.

These ylides are comparable to the cyanide adducts in their ability to

catalyze the Stetter Reaction effectively

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 Sinteza atorvastatina (2/4)

* *
*
aldolna reakcija

preestrenje

Sinteza atorvastatina (3/4)

1. odščita
2. laktonizacija

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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 cerivastatina (1/4)

Knoevenagel

Hantzscheva
sinteza
Michaelova 1,4-dihidropiridinov
adicija

enamin

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 Sinteza cerivastatina (2/4)

Wittig-Horner-Emmons

Wittig-Horner-Emmonsova reakcija

The reaction of aldehydes or ketones with stabilized phosphorus ylides (phosphonate carbanions)
leads to olefins with excellent E-selectivity

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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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Sinteza rosuvastatina (1/2)
Knoevenagel

Sinteza rosuvastatina (2/2)

Wittigova reakcija

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 Učinkovine 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 žolčnih kislin
FENOFIBRAT HOLESTIRAMIN
ETOFIBRAT HOLESTIPOL
BEZAFIBRAT
GEMFIBROZIL • zaviralci lipaze
ORLISTAT
nižajo nivo VLDL v plazmi

Sinteza fenofibrata

Friedl-Crafts

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 Učinkovine 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 žolčnih 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 odščita (cepitev tetrahidropiranilnega etra s p-TsOH

nakar sledi estreneje z zaščiteno amino kislino

Ezetimib, orlistat

• obravnavamo pri predmetu EUTOMERI

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