Design and synthesis of piperazine derivatives as a novel class of γ-secretase modulators that selectively lower Aß42 production.

Novel piperazine derivatives as γ-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Aß42 production. Lead compound 3, with selective Aß42-lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j, which selectively reduced brain Aß42 in mice.

Pharmacological characterization of a highly selective and potent partial agonist of the MT2 melatonin receptor.

BACKGROUND/AIMS: The MT2 melatonin receptor is a potential target for treating circadian rhythm sleep disorders. This study aims to characterize the recently identified MT2 melatonin receptor agonist. METHODS: The pharmacological properties of the MT2 melatonin receptor-selective agonist as exemplified by compound 1 [N-(2-[7-benzyl-1,6-dihydro-2H-indeno(5,4-b)furan-8-yl]ethyl)acetamide] were evaluated by use of cell-free binding and cell-based functional assays. RESULTS: Competition binding assays using 2-[(125)I]iodomelatonin revealed rapid, reversible, and high-affinity binding of compound 1 to human, mouse, and rat MT2 melatonin receptors. cAMP, ERK1/2, and PathHunter ß-arrestin recruitment assays revealed partial agonist activities. However, compound 1 induced a more intense internalization of human MT2 melatonin receptor than melatonin. Based on studies using structurally related analogs of compound 1, we further demonstrated that the extent of internalization is independent of the intrinsic efficacy of agonists. CONCLUSION: These findings provide novel insights into the relationship between intrinsic agonist efficacy and agonist-induced internalization and demonstrate that compound 1 could serve as a pharmacological tool for future studies to elucidate the detailed molecular mechanism of MT2 receptor internalization.

Synthesis of a novel series of tricyclic dihydrofuran derivatives: discovery of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridines as melatonin receptor (MT1/MT2) ligands.

Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT(1)/MT(2)) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan 1a. By screening the central tricyclic cores, we identified 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine as a potent scaffold with a high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of the side chains led to identification of the potent MT(1)/MT(2) agonist 4d (MT(1), K(i) = 0.062 nM; MT(2), K(i) = 0.420 nM) with good oral absorption and blood-brain barrier (BBB) penetration in rats. The oral administration of compound 4d exhibited a sleep-promoting action in freely moving cats at 0.1 mg/kg.

1,6-Dihydro-2H-indeno[5,4-b]furan derivatives: design, synthesis, and pharmacological characterization of a novel class of highly potent MT2-selective agonists.

A novel series of 1,6-dihydro-2H-indeno[5,4-b]furan derivatives were designed and synthesized as MT(2)-selective ligands. This scaffold was identified as a potent mimic of the 5-methoxy indole core of melatonin, and introduction of a cyclohexylmethyl group at the 7-position of this scaffold afforded an MT(2)-selective ligand 15 (K(i) = 0.012 nM) with high MT(1)/MT(2) selectivity (799). Compound 15 was identified as a potent full agonist for the MT(2) subtype and exhibited reentrainment effects to a new light/dark cycle in ICR mice at 3-30 mg/kg. This result demonstrated the involvement of the MT(2) receptors in chronobiotic activity.