HTN Med Chem (Cut off for Exam 2)

Question 1

Thiazide Pharmacophore

Answer 1

• Binds at Cl- receptor site on the Na+/Cl- symporter
• Mimics benzothiadiazide nucleus
• MUST have an electron withdrawing group, donating group decreases activity about 20x
• Ideal to NOT have a double bond between C3 and N4

Question 2

Thiazide SAR: Potency

Answer 2

• C3-N4 saturation (no double bonds, increases activity 10x)
• C3 - lipophilic group (more lipophilic, more potent)
• C6 - EWG (-Cl or -CF3, one isn’t better than the other)

Question 3

Thiazide SAR: Duration

Answer 3

• Increased lipophilicity
• C3 - lipophilic group
• N2 - alkyl group (-CH3)