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In vitro metabolism studies on a series of 3,5-bis(trifluoromethyl)benzyl ethers have identified 3,5-bis(trifluoromethyl)benzoic acid as a significant metabolite possibly arising via oxidation of the benzylic position. A methyl group was introduced in an effort to suppress this route of metabolism. One diastereoisomer displayed an increase in affinity and a marked improvement in duration of action. In vitro metabolism studies on a series of 3,5-bis(trifluoromethyl)benzyl ethers have identified 3,5-bis(trifluoromethyl)benzoic acid as a significant metabolite possibly arising via oxidation at the benzylic position. A methyl group was introduced in an effort to suppress this route of metabolism. One diastereoisomer displayed an increase in affinity and a marked improvement in duration of action

The effect of nitrogen substitution on the binding affinity of the piperidine-ether substance P antagonist L-733,060 for the hNK 1 receptor and L-type Ca 2+ channel is discussed.

The synthesis of a new series of piperidine-based ethers is described and the relative and absolute stereochemical requirements necessary for high affinity binding to the hNK1 receptor established. The synthesis of the corresponding pyrrolidine derivative is also presented.

An exploration of benzhydryl replacements is described. Whilst bridged and fused polynuclear aromatic systems both incur a reduction in affinity it was possible to replace the benzhydryl by a single phenyl ring with only a modest reduction in affinity. In contrast to the analogous diphenylalanyl ethers the binding was also shown to be stereoselective.

A series of 2-aminoethyl ethers based on diphenylalaninol have been shown to have significant affinity for the human NK 1 receptor and reduced affinity at the L-type Ca ++ channel compared with quinuclidines related to CP 96,345.

The in vitro activies of 4-substituted and bicyclic analogues of the glycine-site NMDA partial agonist HA-966 (1) reveal strict structure-activity requirements reflecting subtle conformational and steric requirements for receptor binding. The most active compounds have cis-4-methyl or hydroxyl substituents and it is suggested that the in vivo anticonvulsant activity and good brain penetration of the optimal compound (+) 2 (L-687,414) result from the high fraction of (+) 2 which is not ionised at physiological pH.

A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.

The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent γ-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain Aβ in transgenic mouse models and thus have potential as possible treatments for Alzheimer’s disease.

A series of novel spiroether-based neurokinin-1 (NK 1 ) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.

A series of novel spiroketal-based NK(1) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.

The design and syntheses of new series of gem -disubstituted pyrrolidine and piperidine derivatives (eg. 2 and 3 ) is described. The design and syntheses of new series of gem -disubstituted pyrrolidine and piperidine derivatives (eg. 2 and 3 ) is described.