Keele Medicinal Chemistry Rational Drug Design: Ace Inhibitors

Front 1

What is the normal blood pressure range?

Back 1

<130mm Hg systolic over <85mm Hg diastolic

Moderate=

160-180 over 100-110

Front 2

What causes primary hypertension?

Back 2

No obvious cause, but family history, smoking, alcoholism and obesity may predispose patient

Front 3

What causes secondary hypertension?

Back 3

Renal disease, tumours, drug side-effects, pregnancy

Front 4

What is Isolated systolic hypertension?

Back 4

-Occurs mostly in elderly patients over 60

-Systolic>160mm Hg; diastolic within normal limits

-Associated with high incidences of strokes

Front 5

What is the Baroreceptor mechanism?

Back 5

-Pressure sensing areas throughout vasculature

-Alters the autonomic outflow

-Continuous monitoring, fast response

Front 6

What does the Renin-Angiotensin system do?

Back 6

Control pressure long term

Front 7

What is renin?

Back 7

Proteolytic enzyme

Front 8

Where is Renin secreted from?

Back 8

Juxtaglomerular cells in the kidney

Front 9

What causes an increase in renin secretion?

Back 9

-A fall in Na+ concentration

-A fall in renal perfusion pressure

-Beta-adrenoreceptor agonists

-Prostacyclin

Front 10

What causes the inhibition of Renin?

Back 10

-Angiotensin II (feedback control)

-Atrial natriuretic peptide

Front 11

What occurs in the Renin-Angiotensin System?

Back 11

• Renin, a proteolytic enzyme, is secreted into the blood in the kidneys by the juxtaglomerular apparatus• Angiotensinogen is produced by the liver• Renin cleaves angiotensinogen to give angiotensin I• Angiotensin Converting Enzyme (ACE) cleaves angiotensin I to give angiotensin II during passage through the lungs• Angiotensin II constricts the renal efferent arteriole greater than the afferent arteriole• Angiotensin II increases or maintains the glomerular filtration pressure• High levels of aldosterone conserve salt and water and therefore increase blood volume• Increased angiotensin II levels is often a physiological response to renal artery stenosis

Front 12

What is the angiotensin converting enzyme?

Back 12

Endothelial cell membrane-bound glycoprotein

Front 13

What is the Mr of ACE?

Back 13

129 kDa, 26% polysaccharide

Front 14

How many Zinc atoms are there per active site on ACE?

Back 14

One Zn atom per active site

Front 15

What year was the primary structure of ACE determind?

Back 15

1988

Front 16

What does ACE create?

Back 16

Angiotensin II

Front 17

What does ACE inactivate?

Back 17

Bradykinin

Front 18

What does the inhibition of ACE do?

Back 18

Lowers blood pressure

Front 19

From what animal were a range of ACE inhibitors isolated from?

Back 19

The Brazilian Arrowhead viper

Front 20

What is the most potent ACE inhibitor found in the Brazillian Arrowhead viper?

Back 20

Teprotide

Front 21

What do ACE and carboxypeptidase A have in common?

Back 21

-Both are exopeptidases which cleave residues from the ends of a protein

-Both enzymes require a free C-terminal CO2H

-Neither will hydrolyse an imino-acyl bond

-Neither will hydrolyse a peptide which has a C-terminal dicarboxylic acid

-The active site of both enzymes contains zinc

Front 22

What is an imino-acyl bond?

Back 22

An amide/peptide bond where the NHR component is proline

Front 23

What does ACE have a high affinity for?

Back 23

Peptides with an aromatic amino acid in the antipenultimate position

Front 24

What was chosen as the C-terminus residue following results with BPP5a and Teprotide?

Back 24

Proline

Front 25

What's the difference between the Zn site of ACE and Carboxypeptidase A?

Back 25

The Zn site is further away from the carboxyl binding site in ACE

Front 26

What is required for strong binding to the substrate in ACE?

Back 26

Two hydrophobic pockets

Front 27

What should be hydrogen-bonded to the enzyme in ACE?

Back 27

The non-scissile amide bond

Front 28

What is Captopril?

Back 28

The first orally active ACE inhibitor

Front 29

What are the features of Captopril?

Back 29

Tightly binding, competitive inhibitor not active against other peptidases at concentrations <10^-3 M-> specific for ACE

Front 30

What is the half life of captopril?

Back 30

2 hours

Front 31

What are the side effects of ACE inhibitors?

Back 31

Hypotension, cough, hyperkalemia, renal failure, fetal anomalies, angioedema

Front 32

What are the side effects specific to the thiol group in captopirl?

Back 32

Neutropenia, rash, nephrotic-range proteinuria, taste disturbances

Front 33

What is enalapril?

Back 33

A pro-drug

Front 34

How is enalaprilat formed?

Back 34

By the metabolic processing of the pro-drug enalapril in the liver