Colin J. Theobald

N-1 substituted pyrimidin-4-ones: Novel, orally active inhibitors of lipoprotein-associated phospholipase A2

From two related series of 2-(alkylthio)-pyrimidones, a novel series of 1-((amidolinked)-alkyl)-pyrimidones has been designed as nanomolar inhibitors of human lipoprotein-associated phospholipase A2. These compounds show greatly enhanced activity in isolated plasma. Selected derivatives such as compounds 51 and 52 are orally active with a good duration of action.

2-(Alkylthio)pyrimidin-4-ones as novel, reversible inhibitors of lipoprotein-associated phospholipase A2.

Starting from two weakly active hits from high throughput screening, a novel series of 2-(alkylthio)-pyrimidin-4-ones with high potency and selectivity for lipoprotein-associated phospholipase A2 has been designed. In contrast to previously known inhibitors, these have been shown to act by a non-covalent and substrate competitive mechanism.

Iodobolpyramine and other iodinated derivatives as ligands for detecting histamine H1 receptors

Abstract The synthesis is described of potential I-labelled H 1 -receptor ligands. Receptor affinity is assessed in vitro from inhibition of histamine-stimulated contraction of guinea pig ileum and/or through binding to guinea pig cerebellar membranes. Direct iodination of mepyramine and of hydroxy analogues of mepyramine and temelastine (SKF the compound is purified by TLC and authenticated by HPLC comparison with non-radiolabelled mono- and di-iodinated bolpyramine derivatives. Cyanobutyl-and acetamidopentyl-analogues of mepyramine are also tested as histamine antagonists and structure—activity relationships are described.

Non-basic histamine H1-antagonists. I. Synthesis and biological evaluation of some substituted 2-(2-pyridylaminoalkylamino) pyrimidones and related compounds

Abstract Using the combined H 1 /H 2 -receptor histamine antagonist, icotidine (SK&F 93319, 5b ) as a starting point, a series of pyridylaminoalkylaminopyrimidones has been evaluated as potential selective H 1 -receptor antagonists with low ability to penetrate the CNS. The most potent compound, SK&F 94070, 34 , 2-[3-(5-chloro-3-methyl-2-pyridyl-amino) propylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone is shown to be a highly selective H 1 -receptor antagonist of potency comparable with classical antihistamines, both in vitro and in vivo . This compound, which has no strongly basic centre and is mainly unprotonated at physiological pH, most likely binds to the receptor as a neutral (uncharged) molecule. It exemplifies a new structural type of antagonist which represents an important departure from the conventional view of antihistamines as strongly basic amines which are predominantly protonated under physiological conditions and believed to interact with the receptor in the cationic form.