1. Medicinal Chemistry 2

Why were angiotensin II receptor blockers (ARBs) developed?

• ACE inhibitors lower BP but cause bradykinin build-up in the lungs, leading to a persistent dry cough.

• ARBs block the angiotensin II receptor to lower BP without causing the cough.

Why were peptides like Saralasin not ideal as angiotensin II receptor blockers (ARBs)?

• Peptides are polar and charged at intestinal pH, making them poorly bioavailable.

• They have a short duration of action.

• Saralasin, a peptide, has partial agonist activity, which is not ideal for ARBs.

What did SAR studies reveal about Angiotensin II binding?

• The C-terminal (RHS) region of Angiotensin II is the most important for binding.

• Imidazole-5-acetic acid analogs, like S-8038, showed antihypertensive activity.

• These analogs blocked the receptor without agonist activity by forming non-covalent interactions with the receptor.

How was S-8038 improved to Losartan?

• Variants were made to improve potency, with the black part being less important.

• A carboxylic acid at the para position increased potency but caused charge issues.

• Converting the carboxylic acid to an alcohol reduced the charge.

• Adding an amide group and using ortho isomers improved potency.

• A bioisostere (tetrazole) mimicked the carboxylic acid, enhancing binding and bioavailability.

What is a bioisostere and how is it applied in drug design?

• Bioisosteres are compounds or groups with similar molecular shapes, volumes, and electron distribution.

• A replacement functional group mimics the original in shape and charge, maintaining the desired biological activity.

• Example: A tetrazo ring replaces a carboxylic acid group, with subtle differences like charge delocalization over five atoms.

• This modification improves bioavailability, stability, and reduces metabolism, making the drug more effective.

• The change in properties (e.g., pKa) enhances the drug's performance while keeping its biological function.

What is significant about losartan's metabolite?

• Losartan's metabolite, EXP-3174, is an active compound.

• It is a potent receptor antagonist, with no partial agonism.

• EXP-3174 is 40 times more potent than losartan itself.

What are second-generation ARBs, and how are they improved compared to earlier versions?

• Second-generation ARBs have structural modifications for better potency and receptor binding.

• They keep the central scaffold but modify functional groups.

• Example: A carboxylic acid is replaced by a theophany (a five-membered sulfur ring) to mimic the carboxylic acid group.

• Improvements include:

  • Enhanced potency (low nanomolar range)

  • Better bioavailability

  • Molecular weight under 500 Dalton for oral absorption

  • Hydrogen bond donors/acceptors for receptor interaction

  • Often given as a salt to reduce charge and improve absorption.