A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease.

We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.

Discovery, synthesis, and structure-activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists.

Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4'-fluoro-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity.

T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist.

Through the screening of our in-house chemical compound library, we found a novel melanin-concentrating hormone (MCH) receptor antagonist, T-226296, a (-) enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fluoro[1,1'-biphenyl]-4-carboxamide. T-226296 exhibited high affinity for cloned human and rat MCH receptors (SLC-1) in receptor binding assays (IC50=5.5+/-0.12 nM for human SLC-1; 8.6+/-0.32 nM for rat SLC-1). T-226296 had high selectivity over other receptors, including the second subtype of the MCH receptor, SLT (MCH2), transporters and ion channels. In Chinese hamster ovary (CHO) cells expressing human SLC-1, T-226296 reversed the MCH-mediated inhibition of forskolin-stimulated cAMP accumulation, inhibited MCH-induced intracellular Ca2+ increase, and also inhibited MCH-stimulated arachidonic acid release. In rats, oral administration of T-226296 (30 mg/kg) almost completely suppressed the food intake induced by intracerebroventricular injection of MCH. These results clearly indicate that T-226296 is a novel, orally active and selective MCH receptor antagonist that will be promising for further exploring the physiology and pathophysiology of MCH-SLC-1 signaling.

Melanin-concentrating hormone receptor 1 antagonists. Synthesis and structure-activity relationships of novel 3-(aminomethyl)quinolines.

It was found that 3-(aminomethyl)quinoline derivatives showed high binding affinities for melanin-concentrating hormone receptor 1 (MCHR1) with reduced affinity for serotonin receptor 2c (5-HT2c) when the dihydronaphthalene nucleus of compound 1 (human MCHR1, IC(50) = 1.9 nM; human 5-HT2c receptor, IC(50) = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC(50) = 0.54 nM), potent in vitro antagonistic activity (IC(50) = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC(50) > 1000 nM). Oral administration of 5v significantly and dose-dependently suppressed nocturnal food intake in diet-induced obese rats and did not affect food intake in MCHR1-deficient mice. These results and rat pharmacokinetic study findings suggested that compound 5v is a highly potent, orally bioavailable, and centrally acting nonpeptide MCHR1 antagonist.

Ameliorative effects of a non-competitive BACE1 inhibitor TAK-070 on Aß peptide levels and impaired learning behavior in aged rats.

We examined the effects of TAK-070, a novel non-competitive ß-secretase (BACE1) inhibitor, on the levels of Aß peptides and behavioral deficits in rats. TAK-070 reduced soluble Aß40 and Aß42 levels of the cerebral cortex in a time- and dose-dependent manner in young rats. We found that the insoluble Aß42 content increased significantly with aging from 22 months old without changing Aß40 content. TAK-070 normalized the Aß42 levels to those in young rats when they were fed chow containing TAK-070 starting at 19 months old for 6.5 months. Repeated administration of TAK-070 to aged rats for 2 weeks ameliorated the impaired spatial learning in the Morris water maze task and reduced the levels of soluble and insoluble Aß peptides at doses of 0.3-1mg/kg, (p.o.). Interestingly, TAK-070 significantly recovered the reduced brain synaptophysin levels in aged rats to those in young rats. Our findings support the idea that partial inhibition of BACE1 by TAK-070 exerts symptomatic as well as disease-modifying effects for the treatment of Alzheimer's disease.