SAR of calcium channel blockers

 The Structure-Activity Relationship (SAR) of calcium channel blockers (CCBs) helps us understand how variations in the chemical structure of these drugs influence their potency, selectivity, and pharmacokinetic properties. CCBs are primarily classified into three main classes:

1. Dihydropyridines (e.g., Nifedipine, Amlodipine)
2. Phenylalkylamines (e.g., Verapamil)
3. Benzothiazepines (e.g., Diltiazem)

1. Dihydropyridines (DHPs)

• Core Structure: The DHPs have a dihydropyridine ring as their core structure. The activity of DHPs depends heavily on the substituents attached to this ring.

• SAR Highlights:

  • Substituents at the C4 position: Most commonly, an aryl or substituted aryl group (e.g., phenyl, ortho or meta-substituted phenyl) is attached. This influences binding affinity to the L-type calcium channel.
  • Ester groups at C3 and C5 positions: Ester functional groups are crucial for activity and lipophilicity, influencing both absorption and metabolism. They contribute to the overall hydrophobic nature, which is vital for calcium channel binding.
  • C2 and C6 positions: These positions typically contain methyl or small alkyl groups. The steric properties and hydrophobicity here affect drug metabolism and interaction with the channel.

• Key Pharmacophore: The dihydropyridine ring with ester groups at positions C3 and C5 and an aryl group at C4 forms the basic pharmacophore responsible for the calcium antagonistic activity.

2. Phenylalkylamines (Verapamil-like)

• Core Structure: The structure of phenylalkylamines consists of a benzylamine scaffold.

• SAR Highlights:

  • Aromatic ring: The phenyl ring contributes to the hydrophobic interactions necessary for binding to the calcium channel.
  • Amino group (alkylamine chain): Essential for activity, as it plays a role in interacting with the channel and enhancing selectivity towards cardiac tissues.
  • Substituents on the aromatic ring: These influence selectivity for cardiac versus vascular tissues and also impact the drug’s binding kinetics.

• Key Pharmacophore: The aromatic ring and the nitrogen-containing side chain are essential for calcium channel blocking activity, particularly in the heart.

3. Benzothiazepines (Diltiazem-like)

• Core Structure: Benzothiazepines feature a benzothiazepine ring system.

• SAR Highlights:

  • Benzene ring (aromatic ring): Provides hydrophobic interactions with the calcium channel.
  • Nitrogen and sulfur atoms: The presence of these heteroatoms in the core structure influences binding and metabolism.
  • Substituents on the benzene ring: Similar to DHPs and phenylalkylamines, these substituents can enhance selectivity for vascular versus cardiac tissue.

• Key Pharmacophore: The benzothiazepine ring, along with the correct substituents, determines the compound's ability to block calcium channels, with activity focused on both cardiac and vascular tissues.

General SAR Features Across All Classes:

• Lipophilicity: The more lipophilic the compound, the better it can cross cell membranes and bind to the intracellular L-type calcium channel.
• Substituent variation: Modifying groups attached to the core scaffold (aryl, alkyl, or amine) can modulate selectivity between cardiac and vascular tissues, as well as influence pharmacokinetics (e.g., oral bioavailability, metabolism).
• Stereochemistry: In some cases, stereochemistry at certain positions plays a crucial role in determining drug potency (e.g., S-enantiomers of some DHPs may be more active than R-enantiomers).

These structural variations allow for selective targeting of blood vessels, the heart, or both, and enable the development of drugs with specific therapeutic profiles, like antihypertensive action or antianginal effects.