Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine.
In the histamine H2-receptor antagonist metiamide (2a) isosteric replacement of thione sulfur (=S) by carbonyl oxygen (=O) or imino nitrogen (=NH) affords the urea 2c and guanidine 2d which are antagonists of decreased potency. The guanidine is very basic and at physiological pH is completely protonated. However, introduction of strongly electronegative substituents into the guanidine group reduces basicity and gives potent H2-receptor antagonists, viz. the cyanoguanidine 2b (cimetidine, "Tagamet") and nitroguanidine 2e. A correspondence between the activity of thioureas and cyanoguanidines is demonstrated for a series of structures 1-4. The close correspondence between cyanoguanidine and thiourea in many physicochemical properties and the pharmacological equivalence of these groups in H2-receptor antagonists leads to the description of cyanoguanidine and thiourea as bioisosteres. Acid hydrolysis of the cyanoguanidine 2b yields the carbamoylguanidine 2f at ambient temperatures and the guanidine 2d at elevated temperatures. Cimetidine is slightly more active than metiamide in vivo as an inhibitor of histamine-stimulated gastric acid secretion and has clinical use in the treatment of peptic ulcer and associated gastrointestinal disorders.
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004355:Drug Stability; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis / Q000494:pharmacology
D006146:Guanidines; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D013890:Thiourea