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Year 2
Diabetes
MEDCHEM DIABETIC DRUG
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Treatment
of type II diabetes
Diagnosis
- levels of glycosylation of haemoglobin (HbA1c), proportional to
glucose
levels in the bloodstream
Diagnosis
- glucose tolerance test, in vivo clearance of
glucose
Treatment
- lifestyle changes: diet, weight, physical activity
Treatment
- medication: monotherapy with metformin or sulfonylureas
Treatment
- medication: monotherapy with other oral drugs
Treatment
- medication: combination of oral drugs
Treatment
- medication: combination of oral drugs and insulin
View source
Synthesis and mechanism of action of metformin
Inhibition of
mitochondrial complex
I - reduces ATP levels, increases
AMP
levels, reduces NAD+ levels
Decreased gluconeogenesis
Stimulation of
AMP-activated protein kinase
Inhibition of
adenylate cyclase
View source
Metformin as a drug
Inexpensive and well tolerated at the clinical dose (>1 g daily)
Often more effective at reducing glucose levels than other antidiabetic drugs
Requires endogenous insulin for action, hence effective only if functional pancreatic islet cells are present
Does not cause hypoglycaemia or weight gain
Gastrointestinal side-effects and, in rare cases, lactic acidosis
Can be used in combination with other oral antidiabetic drugs or insulin
Potential benefits against cancer and ageing, popular self-medication
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Sulfonylureas
glibenclamide
gliclazide
glimepiride
glipizide
tolbutamide
View source
Meglitinides
nateglinide
repaglinide
View source
Mechanism of action of sulfonylurea drugs
Pancreatic KATP
channels are hetero-octamers of four Kir6.2 subunits, which form the
K+ conducting pore
, and four regulatory SUR1 subunits
Upon
glucose stimulation
, the ion channel is closed, leading to influx of Ca2+ and insulin secretion
Sulfonylureas and meglitinides bind to SUR1 and block the ion channel, having the same effect as
glucose
to stimulate insulin secretion
View source
Sulfonylureas as drugs
Inexpensive
,
first
class of oral antidiabetic drugs, in clinical use since the 1940s
Major side effects are
hypoglycaemia
and
weight
gain
Duration of action (
short
, medium or
long
acting) can be tailored to patient response
Work by stimulating
insulin
secretion, hence effective only if functional
pancreatic
islet cells are present
Can be used in combination with other oral antidiabetic drugs or
insulin
View source
Meglitinide antidiabetic drugs
Discovered by medicinal chemistry efforts to find alternatives to
sulfonylureas
that work on the same target (pancreatic
KATP
channels)
Weaker
binding and
faster
dissociation compared to sulfonylureas
Similar side effects of
weight
gain and
hypoglycaemia
but less pronounced than with sulfonylureas
Short-acting,
rapid
onset of action
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The structure of starch
Polymerisation of
glucose
through 1,4 and 1,6 linkages gives starch, an energy storage form of
glucose
Starch is broken down into
glucose
by two hydrolysing enzymes,
a-amylase
and a-glucosidase (a-amyloglucosidase)
Inhibition of the hydrolysis of
dietary
starch will reduce the absorption of
glucose
View source
Acarbose
mechanism of action
Acarbose
mimics
the oligosaccharides formed from starch as well as the transition state of the enzyme
a-glucosidase
Acarbose is a
competitive
inhibitor of
a-glucosidase
View source
PPARg agonists
pioglitazone
View source
SGLT2 inhibitors
canagliflozin
dapagliflozin
empagliflozin
View source
Discovery of
SGLT1
and
SGLT2
Used in
1899
to lower
glucose
levels in a diabetic patient, mechanism unknown
The
kidney
normally reabsorbs all of the
filtered glucose
(~180 g/day)
Reabsorption by two
sodium-dependent glucose co-transporters
(SGLTs) located on the
View source
SGLT2 inhibitors
Canagliflozin
,
dapagliflozin
, empagliflozin
View source
SGLT1 and SGLT2
Sodium-dependent
glucose
co-transporters located on the luminal epithelium in the
kidney tubules
SGLT2: low affinity, high capacity, in the
early proximal tubule
, reabsorbs ~90% of the
filtered glucose load
SGLT1:
low capacity
, in the more
distal
regions of the tubule, absorbs the remaining ~10%
Rate of reabsorption
20-40
% higher in
diabetics
compared to normal individuals
View source
SGLT2 inhibitors as drugs
Not associated with
weight gain
, likely to promote some weight loss due to
reduced glucose reabsorption
Not associated with
hypoglycaemia
Effect independent of
insulin
Results in
glycosuria
(≥
50
g/ day)
Potential for
side-effects
due to
glycosuria-
tiredness, dehydration, urinary tract infections
View source
GLP-1
, an
incretin
hormone
Incretins are
GI
hormones that are secreted in response to nutrient stimuli and stimulate
glucose-dependent
insulin secretion
GLP-1
itself is rapidly cleaved (t1/2 1-2 min) to an inactive form by the
serine protease dipeptidyl peptidase 4
(DPP-4)
Increase
insulin
production and secretion
Decrease
glucagon secretion
Slow
gastric
emptying
Promote
weight
loss by inducing
satiety
View source
GLP-1
signaling in the b-cell
GLP-1
binds to the
GLP-1
receptor, a GPCR coupled to adenylyl cyclase
Triggers Epac2, EGFR, PI3K and
CHOP
pathways to induce
insulin
secretion, proliferation of b-cells and suppression of apoptosis
View source
Extending the lifetime of GLP-1 signaling
Modify
the
structure
of GLP-1 so that it is less easily broken down
Replacing the
alanine
by
glycine decreases
cleavage by DPP-4
Modify
the
structure
of GLP-1 so that it hides from DPP-4
Binding GLP-1 to
albumin
or other proteins increases stability
Inhibit the
protease
DPP-4
DPP-4 inhibition increases the lifetime of
endogenous
GLP-1
View source
Albiglutide
, an albumin conjugate of human
GLP-1
Two copies of
GLP-1
modified to increase resistance to DPP4, conjugated with
albumin
protein
Once weekly administration by
subcutaneous
injection
Produced by
fermentation
in recombinant strain of
baker's yeast Saccharomyces cerevisiae
View source
Dulaglutide, an
IgG
conjugate of human
GLP-1
Two copies of
GLP-1
, modified to increase resistance to DPP4, conjugated with
IgG4 Fc
fragment
Once weekly administration by subcutaneous injection, plasma half-life ~
5
days
Manufactured by cell
fermentation
, marketed by
Lilly
View source
Irreversible DPP-4 inhibitors
Cyanopyrrolidines
found to be proline mimetics that covalently bind to
DPP-4
via the active site Ser
Stability improved by
steric shielding
of the
amine
Vildagliptin
(Novartis): MW 303, Clog P 1.1, HBA 4, HBD 2, nrot 3, TPSA 76
Å2
Saxagliptin (Bristol-Myers Squibb): MW 315, Clog P 0.9, HBA 4, HBD
2
, nrot
2
, TPSA 90 Å2
View source
Reversible DPP-4 inhibitors-
sitagliptin
Sitagliptin
(Januvia, Merck)- first in class DPP-4 inhibitor, launched in
2006
, blockbuster drug: MW 407, Clog P 2.0, HBA 4, HBD 1, nrot 5, TPSA 77 Å2
View source
Reversible DPP-4 inhibitors-
linagliptin
and
alogliptin
Linagliptin (FDA approval 2011, EMEA approval
2012
): MW
473
, Clog P 2.6, HBA 7, HBD 1, nrot 5, TPSA 114 Å2
Alogliptin (FDA/EMEA approval 2013): MW
339
, Clog P 0.7, HBA
5
, HBD 1, nrot 3, TPSA 94 Å2
View source
GLP-1 agonists and DPP-4 inhibitors as drugs
Dual effect of promoting
insulin
production in b-cells and inhibiting
glucagon
production in a-cells
Not associated with
weight gain
, in fact GLP-1 agonists are associated with
weight loss
Low risk of
hypoglycaemia
GLP-1 agonists are
injectable
whereas DPP-4 inhibitors are
oral
Drug
overdose
is more problematic with GLP-1 agonists compared to DPP-4 inhibitors
Small but statistically significant risk of
pancreatitis
and
pancreatic
cancer
View source
Mechanism of action of antidiabetic drugs
Insulin
secretagogues: sulfonylureas, metiglinides, GLP-1 agonists, DPP-4 inhibitors
Decrease
glucose absorption: a-glucosidase inhibitors
Decrease
glucose reabsorption: SGLT2 inhibitors
Decrease
gluconeogenesis: metformin, PPARg agonists
Increase
glucose uptake: metformin, PPARg agonists
View source
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