Cardiovascular drugs
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Reasons for using cardiac medications:
Angina Hypertension Arrythmias Cardiac failure Fluid retention leading to cardiac conditions
Family of β-blockers like propranolol:
Aryloxypropanolamines
Excess cholesterol leads to…
cardiovascular disease.
Cholesterol and other fatty molecules are transported around blood supply by _________________________________.
low-density lipoprotein and high-density lipoprotrein
LDLs carry chlosterol from…
the liver to cells.
HDLs carry cholesterol from…
cells to liver.
What are statins?
Statins are drugs that inhibit the enzyme HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) in the biosynthetic pathway to cholesterol. (Inhibit step 2)
What is the goal of statins?
To prevent synthesis of cholesterol within cells by tergeting the enzyme catalyzing the rate limiting step in the biosynthetic pathway of cholesterol.
What reaction does HMG-CoA reductase catalyse?
The rate-limiting in cholesterol biosynthesis: the four-electron reduction of (S)-HMG-CoA into (R)-mevalonate.
Describe the relevant step in the mechanism of action of HMG-CoA reductase.
The reaction begins with HMG-CoA bound tightly in the catalytic pocket. The Carbonyl Attack: The nicotinamide ring of the first NADPH molecule transfers a hydride ion directly to the carbonyl carbon of the thioester group on HMG-CoA. Charge Stabilization: As the carbonyl double bond breaks, Lys-691 positions itself to stabilize the developing negative charge on the oxyanion. Protonation: Concurrently, Glu-559 acts as a general acid catalyst, donating a proton to the oxyanion. This forms the first stable tetrahedral intermediate: mevaldyl-CoA.
What’s the idea behind designing statins?
To mimic melvaldyl-CoA, the tetrahedral intermediate.
What are the structural ideas in statins?
Every statin must contain a 3,5-dihydroxyheptanoic acid chain. The OH groups must be in the R configuration and the carboxylate is IMPORTANT. The R group on C5 is usually a hydrophobic ring or a heterocycle.
What’s the difference between Type I statins and Type II statins?
Type statins are administered as inactive lactone rings. While Type II statins are administered in their active, open-ring hydroxy-acid form.
Describe the mechanism of action of statins.
Statins mimic mevaldyl CoA, preventing it from converting into melavonate. They have the same binding interactions in the polar head group as the natural substrate and they bind more strongly, but they do not undergo a reaction because they lack a leaving group. This stops the upstream synthesis of cholesterol.
Angiotensinogen produced from the liver is converted to ______________________ by the enzyme _________________ (produced in the kidneys).
angiotensin I, renin
Angiotensin I is converted to _________________________ by the enzyme ________.
angiotensin II, ACE
What kind of enzyme is angiotensin converting enzyme (ACE)?
A zinc metallo protease.
How does ACE convert angiotensin I into angiotensin II?
By cleaving the second amide bond from the carboxyl terminus of angiotensin I. It cuts two amino acids off.
How was the first ACE inhibitor produced, Captopril?
By structure-based drug design.
What are the main ideas behind Captopril’s drug design?
It must have a zinc binder and Sulfur does that. It must have a hydrophobic group and H-bond acceptor; and (S) proline did that. It must have a good spacer between the sulfur and proline; and -(CH2)2- did that.
How was Captopril optimized?
With a hydrophobic group (CH3) in the carbon spacer. This improved the inhibitory effect in ACE.
Describe Captopril’s mechanism of action.
Captopril binds strongly to the active site of ACE. It’s thiol group interacts with the zinc binding site. The methyl group in the 2-carbon spacer fits in a hydrophobic pocket. The carbonyl on (S)-proline forms a hydrogen bond. The pyrroliding ring forms hydrophobic interactions. Terminal carboxylate of (S)-proline forms an ionic bond. This results in lowering of blood pressure.
A calcium channel is an ion channel which displays selective permeability to ______________________.
calcium ions
There are 4 types of calcium channels:
*** L type: Located in skeletal, cardiac, and smooth muscles. T type: found in pacemaker cells (heart) N type: Found in neurons P type: Found in purkinje cells.