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) 0.4 microM) and has good selectivity and excellent PK properties.

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.

2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines: functionally selective GABAA alpha3-subtype agonists.

Novel synthetic routes have been devised for the preparation of previously inaccessible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines 2. These compounds are high affinity ligands for the GABA(A) benzodiazepine binding site and some analogues show functional selectivity for agonism at alpha3-containing receptors over alpha1-containing receptors with the lead compound being 32.

Discovery of imidazo[1,2-b][1,2,4]triazines as GABA(A) alpha2/3 subtype selective agonists for the treatment of anxiety.

The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.

Imidazo[1,2-b][1,2,4]triazines as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety.

Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described.

7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models.

There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.

Pyrazolopyridinones as functionally selective GABAA ligands.

2,5-Dihydro-3H-pyrazolo[4,3-c]pyridin-3-ones are GABAA receptor benzodiazepine binding site ligands, which can exhibit functional selectivity for the alpha3 subtype over the alpha1 subtype. SAR studies to optimize this functional selectivity are described.

Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.

We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.

2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones: functionally selective benzodiazepine binding site ligands on the GABAA receptor.

2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones are GABAA receptor benzodiazepine binding site ligands with functional selectivity for the alpha3 subtype over the alpha1 subtype. SAR studies to optimise this functional selectivity are described.

Memories are made of this (perhaps): a review of serotonin 5-HT(6) receptor ligands and their biological functions.

The possible role of 5-HT(6) receptor antagonists in the treatment of learning and memory disorders has stimulated significant recent work in this area. The first selective antagonists of this receptor were identified by Roche (Ro 04-6790 and Ro 63-0563) and SmithKline Beecham (SB-271046), although they only had poor to modest brain penetration, respectively. Recently, several structurally different series of selective antagonists have been reported. Glennon s group and Merck Sharp & Dohme have discovered N,N-dimethyl-1-benzenesulfonyl-5-methoxytrypt amine as a reasonably selective, high affinity antagonist, while Allelix have gone on to find that a 6-bicyclopiperazinyl-1-naphthylsulfonylindole had improved affinity and selectivity. Roche have reported subsequently on more lipophilic analogs of Ro 04-6790 that appear to penetrate the brain better. Reversing the sulfonamide linkage of SB-271046 led to a new series of compounds, producing SB-357134, which also had increased CNS penetration. A series of selective partial agonists containing a 4-piperazinylquinoline system has also been described. Recent studies in the Morris water maze with both Ro 04-6790 and SB-271046 have concluded that 5-HT(6) receptor antagonists improved retention performance, although these results are open to interpretation. Other behavioural studies have also implicated a role for 5-HT(6) in cognition enhancement and this has been supported by in vivo microdialysis studies that showed SB-271046 produced an increase in extracellular glutamate levels in the frontal cortex. However, we have been unable to replicate these effects with either SB-271046 or Ro 04-6790, and clearly further work is required before we can be certain of the functional role of this receptor.