Rational drug design: the modern development cycle.
New cardiac drugs:
Heart disease is common and the potential rewards for drug
companies are high, so research continues on a broad front. All stages of the
disease process are under attack, ranging from hypertension, diabetes, blood
lipids, atherosclerosis, thrombosis, clot dissolution, and support for the
failing heart. Heart failure is the most intractable problem: all forms of heart
disease may ultimately lead to heart failure, and currently 50% of patients with
severe heart failure will be dead within 2 years.
Cost-effectiveness is also an important issue.
Gaspoz et al
(2002) NEJM 346, 1800-1806 have pointed out that if appropriate treatment
were offered to all eligible patients, the platelet inhibitor clopidogrel is
currently ten times more expensive than aspirin therapy per quality-adjusted
year of life gained.
Advances in basic research have identified many additional
targets for the drug development cycle. Particular attention has focused on the
signalling mechanisms that maintain normal blood pressure and tissue perfusion
in healthy subjects.
Vasoactive peptides (all of these use seven transmembrane helix receptors)
| peptide name |
produced by
|
actions
|
| adrenomedullin |
everywhere |
vasodilation |
| angiotensin |
renin, ACE (proteases) |
vasoconstriction |
| atrial natriuretic |
right atrium stretch |
increased water and sodium losses by kidney |
| B-natriuretic |
ventricular muscle |
as above |
| C-natriuretic |
vascular endothelium |
as above |
| bradykinin |
kallikrein (protease) |
vasodilation, increased vascular permeability |
| endothelin |
vascular endothelium |
vasoconstriction, bronchoconstriction |
| vasopressin |
posterior pituitary |
increases renal water retention |
| VIP |
parasympathetic nerves |
vasodilation (salivary glands) |
other vasoactive substances
| name |
produced by |
actions |
| adenosine |
all working tissues |
vasodilation |
| adrenaline |
adrenal medulla |
vasodilation (b)
predominates |
| aldosterone |
adrenal cortex |
sodium retention by kidney |
| histamine |
mast cells |
both constriction & dilation (receptors) |
| leukotriene LTC4 |
leukocytes |
vasoconstriction, bronchoconstriction |
| noradrenaline |
sympathetic nerves |
vasoconstriction (a)
predominates |
| nitric oxide |
vascular endothelium |
vasodilator via cGMP |
| prostacyclin PGI2 |
vascular endothelium |
vasodilation, prevents clotting |
| prostaglandin PGE1 / E2 |
macrophages |
both constriction and dilation (receptors) |
| thromboxane TXA2 |
platelets |
vasoconstriction, promotes clotting |
New drugs now being developed for heart failure include
selective aldosterone receptor antagonists, calcium sensitizers, cytokine
inhibitors, endothelin receptor antagonists, growth hormone releasers,
natriuretic peptides, neutral endopeptidase inhibitors, vasopeptidase inhibitors
and vasopressin antagonists.
| drug name |
type |
actions |
| levosimendan |
calcium sensitizer |
enhances troponin Ca++ binding & opens
vascular ATP-sensitive K+ channels |
| |
cytokine inhibitor |
anti-inflammatory |
| bosentan |
endothelin receptor antagonist |
|
| ghrelin |
growth hormone releaser |
|
| nesiritide |
natriuretic peptide |
increases salt and water excretion |
| thiorphan |
neutral endopeptidase inhibitor |
blocks degradation of bradykinin & ANP |
| eplerenone |
selective aldosterone receptor antagonist (SARA) |
blocks aldosterone actions in kidney and in cardiac
muscle (anti-fibrosis) |
| omapatrilat |
vasopeptidase inhibitor |
blocks both angiotesin II formation, and the
degradation of bradykinin and ANP |
| |
vasopressin antagonist |
blocks V2 receptors in collecting ducts |
Adrenomedullin is a potent vasodilator that reduces
blood pressure while increasing cardiac output. Gene knockout shows that it is
essential for normal cardiovascular development. It is produced by many tissues,
including heart and vascular smooth muscle when stimulated by pro-inflammatory
cytokines such as TNF-a, and it exerts a protective
effect in animal models of toxic shock. It probably acts via nitric oxide and
cAMP, but the principal signalling system varies between tissues and species.
There is a
collection of reviews in Microscopy Research and Technique, volume 57 issues
1 and 2, March and April 2002.
Aldosterone is produced by the adrenal cortex when
stimulated by angiotensin II. It causes sodium and water retention by the
kidney, and a urinary potassium losses. It is also regulates salt resorption in
the colon and sweat glands, and promotes collagen synthesis in cardiac muscle
leading to myocardial fibrosis. Spironolactone is a non-specific aldosterone
antagonist that has been in use for several years, but it also binds to sex
steroid receptors leading to unwanted side effects. It is commonly added to
other drug regimes. Eplerenone is a more selective compound that is currently in
phase III clinical trials.
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