Chronic Heart Failure Drug Chemistry

Question 1

SGLT2 inhibitors

Answer 1

• Nephrons reabsorb all filtered glucose through two types of sodium co-transporters SGLT1 and SGLT 2
• Inhibition good for diabetic reduce hyperglycemia

Question 2

Phlorizin

Answer 2

• From bark of apple tree increase glucose in urine

Question 3

Gliflozins SAR

Glycone part

Answer 3

• Reproduce glucose by binding SGLT2 and other sugar substitutions effecting potency and loosing activity

Question 4

Gliflozins SAR

Aglycone part

Answer 4

• Two ring system seperated by spacer CH2 molecule
• Interferance loose activity

Question 5

Gliflozins SAR

Ring system

Answer 5

• Attached to the glycone part through C atom forming C-glycoside
• More selective SGLT2 inhibitor than O-glucoside

Question 6

Gliflozins SAR

R1 Bulkier groups

Answer 6

• Loss of activity due to mono substitution with Cl or F
• Effects potency and selectivity

Question 7

Gliflozins SAR

Distal ring system

Answer 7

• Simple aryl system with mono substitution at para position

Question 8

Nerilysin

Answer 8

• zinc dependant peptidase
• Degradation of arterial ad brain naturetic peptide
• Blood pressure lowering peptide working to reduce blood volume

Question 9

Sacubitril

Answer 9

• Inhibits function of nerilysin decrease degradation of arterial and brain naturitic peptide
• Increase BP lowering function
• Prodrug hydrolysed ester group to carboxylic

Question 10

Neprilysin inhibitor interaction

Answer 10

• Ionic bond formtion with zn2+ and both O- and C=O
• Arg717 and Asn542 forms a hydrogen bond
• Reversible non-covalent interactions
• Two chrial centres and (R) (S) isomer is active other less active
• Hydrophobic interaction

Question 11

Loop diuretics

Answer 11

• Inhibits Na+, K+ and Cl- symports causing an increase in lumen
• Retention of water causes increased urine excreation with high excreation of salts
• family of sulphonomides and phenoxyacetic acid family

Question 12

SAR of loop diuretics
Sulphonamides

Answer 12

• Acidic group in position 1 e.g. carboxylic acid for diuretic activity
• Position 4 can be Cl or alkoxy or aniline to increase activity
• If amino in position 2 with phenyl max activity
• Amino in position 3 is 50 fold more potent if alkyl group present
• Presence of sulphamoyl group in position 5 essential
• Carboxylic acid cause ionisation and PKa 3.9

Question 13

SAR of loop Diuretics phenoxyacetic acid derivatives:
Ethacrynic acid

Answer 13

• Weakly acidic group in para direct drug to kidney
• Alpha/Beta unsaturated carbonyal react with sulphydryl groups
• Lipophilic groups position 2 and 3
• Mono or Non-sub terminal alkene carbon cause maximum reactivity
• Useful to those allergic to sulphonamides