Insulin(s) and other, mostly oral antidiabetics
© Oldřich Farsa 2012
One- and three-letter symbols of L-α-amino acid rests
One-letter Three-letter
A Ala alanine
B Asx asparaginic acid or asparagine
C Cys cysteine
D Asp asparaginic acid
E Glu glutamic acid
F Phe phenylalanine
G Gly glycine
H His histidine
I Ile isoleucine
K Lys lysine
L Leu leucine
M Met methionine
N Asn asparagine
P Pro proline
Q Gln glutamine
R Arg arginine
S Ser serine
T Thr threonine
U Sec selenocysteine
V Val valine
W Trp tryptofane
X Xaa unknown or „other“ amino acid
Y Tyr thyrosine
Z Glx glutamic acid or glutamine (or compounds such
as 4-karboxyglutamic acid 5-oxoproline)
1.Insulines
Insuline
●
Secreted mostly by β-cells of Langerhans islets of pancreas
●Enables utilisation of glucose by cells of body
●First isolated by Banting and Best from dog´s pancreas in 1921
Human insuline
TP
C
COOHF
NS
H
Q N
ES C Y
Y
C
T
A
I
V TVL LG
E SV QI Y CC
KN L R GENH
2
L
F G
G L
FV
E
Q
C
H YL
NH
2
COOH
chain B (30 AA)
chain A (21 AA)
●formed from its precursor proinsuline consisted of 110 AA
10 20 30 40 50 60
MALWMRLLPL LALLALWGPD PAAAFVNQHL CGSHLVEALY LVCGERGFFY TPKTRREAED
70 80 90 100 110
LQVGQVELGG GPGAGSLQPL ALEGSLQKRG IVEQCCTSIC SLYQLENYCN
1-24 signal sequence; 25-54 chain B; 57-87 peptide C; 90-110 chain A
●today produced by recombinant technology, or by partial synthesis from
the porcine one
Insulinum humanum PhEur
●syn. humuline
Bovine (cow´s) insuline
Insulinum bovinum PhEur
●isolation from beef pancreases
Porcine (swine) insuline
Insulinum porcinum PhEur
Insuline analogues
human
aspart
Insulinum aspartum
PhEur
Novorapid ®
●recombinant technology
insulin-lispro
Insulinum lisprum PhEur
●recombinant
Humalog ®, Liprolog ®
insulin-detemir
●
chain B has only 29 AA, tetradecanoyl (myristoyl) attached to LysB29
●recombinant-semi synthetic
Levemir ®
insulin-glargin
Gly21A
-L-Arg30B
-L-Arg31B
-insulin
Lantus®
, Optisulin ®
●
insulin of 1st
choice in diabetes of 2nd
type when oral antidiabetics are not satisfactory
●long T½
, typically administered 1x daily s.c. before sleeping
insulin-glulisin
Apidra ®
Summary of the used insulin analogues
Glucagone
●adversary of insulin
●
peptid consisted of 29 AA from pancreas α-calls supporting cleavage of liver glycogene and
increasing glycaemia
●causes relaxation of smooth gastric muscules similarly to cholinergics
Glucagonum PhEur
●isolated from porcine or bovine pancreases
Glucagonum humanum PhEur
●produced by recombinant technology; AA sequence is identical
●usage: treament of serious hypoglycaemia, X-ray GIT diagnostic etc.
Sulfonylurea derivatives
●1942 hypoglycaemic side effect of antibacterial sulfonamides discovered
●
1955 carbutamide as 1st
p.o. antidiabetic introduced
S
NH NH
O
O O
R
2
R
1
common is struct. fragment of 1-benzenesulfonylurea subst. in the position 4 of the benzene ring and
and on the N3
of urea
R1
= -H or anything
R2
= alkyl, cycloalkyl, heterocycle with max. 10 non-hydrogen atoms
S
NH NH
O
O O
CH3
CH3
S
NH NH
O
O O
NH2
CH3
carbutamide tolbutamide
Sulfonylurea derivatives
CH3
S
O
O
NH
O
NH N
1-(3-Azabicyclo[3.3.0]oct-3-yl)-3-(p-tolylsulfonyl)urea
gliclazide
Diaprel MR ®
●antiradical effects
●
↓ reactivity of platelets, ↑synthesis of prostacyclin in endothel and fibrinolysis
●improves plasmatic antioxidant parameters (SOD, total antioxidant capacity, thiols)
●probably a result of the presence of 3-azabicyclo[3.3.0]octane moiety
Sulfonylurea derivatives of 2nd
generation
●
first prepared in 1970th
, enabled ↓ dosing g → mg
●result of introducing of carbonylaminoethyl fragment into position 4 of the benzene ring
CH3
O Cl
O
NH
S
O
O
NH
O
NH
NH
S
O
O
NH
O
NH
R
2
R
1
O
glibenclamide
CH3 O
O
N
S
O
O
NH
O
NH
O
CH3
CH3
gliquidone
Glurenorm ®
●
an in vitro evidence of PPARγ receptor
stimulation given; as active as pioglitazone in
induction of the PPARγ target gene expression
Glucobene ®
Sulfonylurea derivatives of 2nd
generation
CH3
NO
O
NH
S
O
O
NH
O
NH N
glisoxepide
CH3
N
N
O
NH
S
O
O
NH
O NH
glipizide
Minidiab ®
Sulfonylurea derivatives of 3rd
generation
CH3
CH3
N
O
NH
S
O
O
NH
O
NH H
H CH3
O
glimepiride
Amaryl ®
Mode of action of sulfonylureas: binding to sulfonylurea receptor, which is a part of K+
ATP
complex ⇒ channel closure ⇒ changes of voltage of β-cells membranes ⇒ influx of
Ca2+
⇒ exocytosis of insulin granules
Adverse effects:
●
interference with K+
-ATP channels of the myocard ⇒ impairing of its function
●further development of hypoglycaemia
●
enhancement of apoptosis and exhaustion of β-cells.
Glinides
●structurally relatively heterogenous group
●
mode of action similar to that of sulfonylureas (binding to the same receptor): ↓
conductivity of membranes of β-cells mediated by K+
⇒ depolarisation of membranes
and opening of voltage-gated Ca2+
channels ⇒ ↑ intracellular concentration of Ca2+
⇒ ↑ release of insulin granules
●
stimulation of PPARγ receptor demonstrated in vitro also
CH3
S
O
O
NH
O
NH N
gliclazide
N
O
O
OH
H
H
mitiglinide
2-benzyl-4-[(3aR,7aS)-octahydro-2H-isoindol-2-yl]-
4-oxobutanoic acid
●
1st
glinide
Glinides
CH3
O
Cl
O NH
OH
O
meglitinide
Glinides
CH3
CH3
H
HO
NH
H
OH O
CH3
O
O
NH
H
CH3CH3
N
OH
O
nateglinide repaglinide
●
probably prolong the life of β-cells
●
reduce postprandial ↑ glycaemia in pacients with worsened glucose tolerance ⇒ slow down
thinning of intima media of carotids
●
positive effect on triglycerides and free fatty acids levels in plasma of diabetics of 2nd
type
120 min after meals
Starlix ® Novonorm ®
Biguanide derivatives
CH3 N
CH3
NH
NH
NH2
NH
CH3
NH
NH
NH
NH2
NH
1,1-dimethylbiguanide
Adimet ®
metformin
●also cardioprotective effect; improves
also conditions in chronic heart failure
probably by means of activation of AMPactivated
protein kinase (AMPK) and
subsequently endothelial nitric oxide
synthase (eNOS) and co-activator of
PPARγ receptor (PGC-1α)
1-butylbiguanide
buformin
Biguanide derivatives
NH2
NH
NH
NH
NH
1-(2-phenylethyl)guanidine
fenformin
●obsolete in humans; causes strong lactate acidosisEffects of biguanides:
●
↓ glucose synthesis in liver by gluconeogenesis
●
↑ utilisation of glucose in peripheral organs
●
↓ fatty acids oxidation about 10 – 20 %
Mode of action: activation of AMPK (AMP-activated protein kinase; in absence of insuline,
biguanides renew uptake of glucose in insulin-resistant cardiomyocytes by complementary
activation of AMPK and protein kinase B; this was demonstrated also in hepatocytes and cells
of skeletal musculature
●target site of gluconeogenesis inhibition: glyceralehyde-3-phosphate reductase; biguanides
inhibít expression of the gene for this enzyme
Unwanted effects: lactate acidose: ↓ gluconeogenesis ⇒ accumulation of pyruvate and
NADH, ↓ NAD+
⇒ (lactate dehydrogenase) ⇒↑ lactate productin
Compounds interacting with PPAR receptors
PPAR = peroxisome proliferator- activated receptors – a family of receptors of the cell
nucleus directly linked to DNA
●sensitive to fatty acids; cause changes of transcription, which alter utilisation (catabolism)
of fatty acids and glucose
●activities of the particular subtypes of PPARs take part in regulation of sensitivity to insulin
and obesity symptoms and also in food intake control
●activation of PPARα
↑ lipolysis and fatty acids oxidation; these receptors take part in the
mode of action of fibates
●PPARγ
receptors = key regulators of insulin resistance; take also part in activation of
adipocytes differentiation, ↑ adipogenesis and thus body weight
PPARδ
(=PPARβ
) receptors are engaged in the process of development of obesity, which is
caused by inproper alimentation
●
PPAR agonists are useful as p.o. antidiabetics, partial selective agonists of PPARγ are
the most suitable ones
Thiazolidindiones
(glitazones)
O
OH
NH S
O
O CH3
OHCH3
CH3
CH3
troglitazone
●
withdrawn; ↑ risk of hepatotoxicity; approx. 1.9 % of patients in clinical tests exhibited ↑ of
alanine aminotransferase (ALT) over the triple of the upper limit
Thiazolidindiones
(glitazones)
CH3
N
O
S
O N
H
O
pioglitazone
CH3
N
O
S
O
N
H
O
N
rosiglitazone
Mode of action: stimulation of PPARγ rp. increases sensitivity of cells of peripheral tissues
(fat, muscles) and of liver to insulin ⇒ ↑ insulin-dependent supply of glucose to cells & ↓
release of glucose from liver
●
probably protect β-cells by ↓ of direct glucotoxicity and insulin requirement
Adverse effects: oedema, cardiomegaly, anaemia, haemodilution
Avandia®
●
↓ concentration of glycated haemoglobin
(HbA1c
)
Actos®
●
quite positive effect to blood lipids: ↓ increased
triacylglyceroles, ↑HDL; ↑LDL less than
rosiglitazone
Selective PPARγ modulators
OH
OH
S
O
O
NH
Cl
O
N
Cl
INT-131
●pharmacological profile different from glitazones: minimal stimulation of adipocytes differentiation,
partial activation of target genes PPARγ engaged in do adipogenesis, it simultaneously exhibits
activity to another set of target genes, which is capable to affect directly insulin sensitivity; gain of
glucose tolerance; preclinical evaluation demonstrated lower impact to lungs and heart weights
and total increase of body weight, haemodilution and plasma volume
●clinical studies of the phase II: INT-131 is 8times more active than rosiglitazone, no evidence of
liquids retention and weight gain was acquired
● X-ray crystallography: other way of binding to the receptor than that of glitazones, primarily forms
hydrophobic contacts with the “ligand binding pocket” without direct H-bonds to key amino acids
rests of the helix 12, which are typical for full agonists
Selective PPARγ modulators
O
S
CH3
O
O
OH
N
CH3
O
O
CH3
PAR-1622
●
partial agonist of PPARγ: 37 % of the activity of the full agonist rosiglitazone, does not
interact with PPARδ , 56x more selective to PPARγ than to PPARα
●improves hyperglycaemia
●does not increase blood plasma volume
GLP-1 analogues
GLP-1: Glucagon-like peptide 1 = an intestinal hormone, which together with glucosedependent
insulinotropic polypeptide(GIP)* potentiates insulin secretion induced by food
●potetiates all steps of insulin biosynthesis; has positive impact to function and surviving of
β-cells
●decreases redundant glucose production in liver, slows down stomach emptying leading to
postprandial hypoglycaemia, its central effect leads to appetite decrease (⇒ body weight
loss), probably also positive effects to cardiovascular system
●disadvantages of GLP-1 as a drug: necessity of administration in a continual infusion,
extremely short biological half-time T1/2
= 2 – 3 min (fast decomposition by peptidases) ⇒
need of more stable analogues
*Both are known also as incretins.
GLP-1 analogues
liraglutide
Victoza ® inj. sol.
γ-L-glutamoyl(N-α-hexadecanoyl)-Lys26
, Arg34
-GLP-1(7–37)
●sequence of amino acid rests shares 97 % identity with the fragment 7-37
of the native GLP-1
●strong binding to serum albumin, mutual association of molecules, does not
come under glomerular filtration ⇒ T1/2
= 12.5 hours after s.c. injection
●
improves functions of both α and β cells
α-Glucosidase inhibitors
H
NH
H
H
CH3
O
H
O
H
H
OH
O
H
O
H
H
OH
O
OH
H
OH
H
OH
H OH
H
OH
H
OH
H
OH
OH
H
OH
H
OH
H
OH
O-4,6-Dideoxy-4-{[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino}-α-D-
glucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)-D-glucose
acarbose
Glucobay®
Mode of action of α-glucosidase inhibitors: inhibition of cleavage of α-glycosidic bond ⇒
hydrolysis of poly- and oligosaccharides to monosaccharides inhibited ⇒ ↓ absorption of
saccharides in small intestine ⇒ ↓ glycaemia
●
slow down also emptying of stomach and ↑ postprandial hypotension and heart rate; probably
also by stimulation of GLP-1
●
reduce postprandial ↑ glycaemia in patients with worsened glucose tolerance ⇒ slow down
thinning of intima media of carotids
α-Glucosidase inhibitors
N
OHOH
H
H
H
H
HOH
OH
OH OH
NH
OHOHOH
OH
OHOH
OH
N-(2-Hydroxyethyl)-1-deoxynojirimycin
miglitol
(Glyset ®)
●a piperidine analogue of glucose
●derived from natural nojirimycin from
Streptomyces ficellus
voglibose
(Basen ®)