SAR studies on H2 antagonists containing alkylamino substituted 1,2,5-thiadiazole 1-oxide moieties

• Published in: Farmaco (Società chimica italiana : 1989) 1998-08, Vol.53 (8-9), p.536-540
• Main Authors: Di Stilo, Antonella, Cena, Clara, Lolli, Marco, Sorba, Giovanni, Gasco, Alberto, Bertaccini, Giulio, Pozzoli, Cristina, Adami, Maristella, Coruzzi, Gabriella
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cerebral Cortex - metabolism; Cimetidine - analogs & derivatives; Cimetidine - metabolism; Guinea Pigs; H2 antagonists; Heart Atria - drug effects; Histamine H2 Antagonists - chemistry; Histamine H2 Antagonists - pharmacology; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Radioligand Assay; Ranitidine analogues; Rats; Rats, Wistar; SAR in H2 antagonists; Stomach - drug effects; Structure-Activity Relationship; Thiadiazoles - chemistry
• ISSN: 0014-827X; 1879-0569
• DOI: 10.1016/S0014-827X(98)00059-7

A number of ranitidine analogues in which the diamino-1,2,5-thiadiazole 1-oxide substructure bearing alkyl chains of different length is present as the urea equivalent group, were synthesised and studied for their lipophilic and H2 antagonist properties. Derivatives which displayed a logP≤3 behaved as competitive antagonists of histamine at H2 receptors present on guinea pig right atrium. The remaining more lipophilic members of the series showed an insurmountable antagonism not completely reversible after prolonged washing. A binding study suggested that an increase in the length of alkyl chain gave rise to hydrophobic interactions with the receptor which were responsible for the apparent irreversible H2 antagonism shown by the higher homologues of the series.