Cimetidine

Structure

• Chemical Structure of Cimetidine- C10H16N6S

Mode of action

• Cimetidine, an antagonist of the H2-receptor, prevents histamine from competitively stimulating the H2-receptors found on the gastric parietal cells.

• So, lesser amount of stomach acid is secreted because of stimuli like histamine, food, coffee, and insulin.

Structure-Activity Relationship (SAR) of Cimetidine

• Cimetidine is a histamine H2 receptor antagonist, primarily used to inhibit stomach acid production.

• Its SAR can be summarized as follows:

1.   Imidazole Ring:

• The core structure of cimetidine is an imidazole ring, essential for its activity as an H2 antagonist.

• This ring mimics the histamine structure, allowing cimetidine to bind competitively to the H2 receptors.

2.   Sulfide or Sulfone Group:

• The presence of a sulfide (thiol) or sulfone group adjacent to the imidazole ring is crucial.

• This moiety increases the affinity of cimetidine for the H2 receptor.

3.   Guanidine Group:

• The guanidine group in cimetidine is essential for its activity.

• This group forms ionic bonds with the receptor, stabilizing the cimetidine-receptor complex.

4.  Cyanoguanidine Group:

• The presence of a cyanoguanidine group is important for the drug's specificity and potency.

5.   Methylthioethyl Side Chain:

• The methylthioethyl side chain attached to the imidazole ring is crucial for the drug's activity.

• Alterations in this part of the molecule can significantly affect the drug's potency and specificity.
  

Synthesis of Cimetidine

• The synthesis of cimetidine involves a multi-step process that includes the formation of the imidazole ring and the incorporation of the cyanoguanidine group.

• A simplified version of this synthesis is as follows:

1.   Formation of Imidazole Ring:

CNCH2​CH2​SCN+NH3 ​→ CNCH2​CH2​SC(=NH)NH2​

• This step involves reacting cyanamide with 2-chloromethylthioethane to form a thiourea derivative.

2.   Cyclization to Form Imidazole:

CNCH2​CH2​SC(=NH)NH2 ​+ CH2​O → imidazolederivative 

• The thiourea derivative is then cyclized, often using an aldehyde like formaldehyde, to form an imidazole derivative.

3.   Introduction of Guanidine Group:

imidazolederivative + CN2​H2 ​→ Cimetidine 

• The imidazole derivative is reacted with cyanamide to introduce the guanidine group, resulting in cimetidine.

4.   Formation of Hydrochloride Salt (if necessary):

Cimetidine + HCl → CimetidineHCl 

• If the hydrochloride salt form is desired, cimetidine is treated with hydrochloric acid.

• This synthesis pathway highlights the formation of the crucial imidazole and cyanoguanidine structures in cimetidine. The exact conditions and reagents can vary based on the desired scale of production and purity requirements.

Uses

• Used for the treatment of ulcers, gastroesophageal reflux illness.