N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists.

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.

N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II.

Introduction of selected amine containing side chains into the 3-position of N',2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI(Kr) affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ(90) 7 mg/kg po; plasma Occ(90) 0.

NK1 antagonists based on seven membered lactam scaffolds.

A new class of high affinity hNK1R antagonists based on seven-membered ring cores has been identified. This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo properties.

Novel lactam NK1 antagonists with anti-emetic activity.

A series of 4,4-disubstituted cyclohexylamine NK(1) antagonists containing a lactam ring is described. The compounds are brain penetrant and activity is demonstrated in a ferret emesis model.

Synthesis of vinylogous carbamates by rhodium(II)-catalyzed olefination of tertiary formamides with a silylated diazoester.

Treatment of tertiary formamides with a silylated diazoester in the presence of a rhodium(II) catalyst leads to the formation of 3-amino-2-silyloxyacrylates in good yield. No olefination is observed if a nonsilylated diazo compound is employed. [reaction: see text]

4,4-Disubstituted cyclohexylamine NK(1) receptor antagonists II.

A series of novel 4,4-disubstituted cyclohexylamines as NK(1) receptor antagonists is described: modifications to the amine moiety retain NK(1) receptor binding affinity whilst disrupting I(Kr) affinity.

4,4-Disubstituted cyclohexylamine NK(1) receptor antagonists I.

A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.