Iain Mair Mcdonald

4-Chlorobenzyl sulfonamide and sulfamide derivatives of histamine homologues: The design of potent histamine H3 receptor antagonists

4-Chlorophenylmethanesulfonamide and (4-chlorobenzyl)sulfamide derivatives of histamine homologues were prepared and found to be potent and selective histamine H3 receptor antagonists. High receptor affinity and low differences in the data from the bioassays were achieved with the imidazol-4-ylbutyl analogues.

Achiral, selective CCK2 receptor antagonists based on a 1,3,5-benzotriazepine-2,4-dione template.

Novel, achiral 1H-1,3,5-benzotriazepine-2,4(3H,5H)-diones have been prepared and structurally characterized. These compounds are potent CCK(2) receptor antagonists that display a high degree of selectivity over CCK(1) receptors.

Novel oxathiazinones as gastrin ligands : Unexpected preducts from the schotten-baumann reaction of arylsulphonyl chlorides with derivatives of aspartic acid

Abstract The Schotten-Baumann reaction of arylsulphonyl chlorides with aspartic acid derivatives does not give the expected sulphonamide as the sole product. The unexpected products appear to represent the first examples of a previously unreported series of arylsulphoxo-2,3dehydro-1,2,3-oxathiazin-6-ones and show activity at the gastrin receptor.

2-NAP: a selective, hydrophilic, non-peptide CCKA - receptor antagonist derived from the cholecystokinin C-terminal dipeptide.

Abstract Analogues of the cholecystokinin (CCK) C-terminal dipeptide (32-33, Asp-Phe-NH 2 ) have been prepared and the structure-activity relationships of this series are described. The sodium salt of 2-naphthalenesulphonyl L-aspartyl (2-phenethyl)amide, (2-NAP), displayed high affinity for CCK A receptors by its antagonism of CCK 8 -stimulated guinea-pig gallbladder contraction. In addition, 2-NAP exhibits selectivity with respect to gastrin/CCK B receptors ( > 300-fold) and has a low log P (−0.91, chloroform/buffer).

Inhibitors of Gastric Acid Secretion

The discovery of potent and selective inhibitors of gastric acid secretion now negates the need for surgical intervention in the treatment of many hypersecretory disorders. The side effects associated with cholinergic antagonists has led to their being superseded by the use of selective histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine) and the more potent irreversible proton-pump inhibitors (omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole). Current therapeutic regimes for the treatment of ulcer disease recommend concurrent proton-pump administration while eradicating Helicobacter pylori, a bacterial infection that is strongly associated with ulcer formation. Because achlorhydria increases the likelihood of gastrointestinal infection, current research within this area is now targeting the design of reversible proton-pump inhibitors and CCK2/gastrin-receptor antagonists. These newer therapeutic approaches, however, are unlikely to produce the rapid and potent inhibition of acid secretion realized by the irreverisble PPIs, which in addition have few side effects and a proven track record of success. Key drug developments in the treatment of acid hypersecretion, from the anticholinergic agents to the highly potent and effective proton-pump inhibitors currently in use, are covered in this chapter. Keywords: gastric acid; ulcer; histamine; acetylcholine; CCK2/gastrin; proton pump; H2-receptor antagonist; proton-pump inhibitor