The presenilin containing ␥-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. ␥-Secretase catalyzes the final step in the generation of A␤ 40 and A␤ 42 peptides from APP. Amyloid ␤-peptides (A␤ peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic A␤ peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide ␥-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits A␤ production with low nanomolar potency in cellular and cell-free assays of ␥-secretase function, and displaces a tritiated analog of GSI-953 from enriched ␥-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid A␤ levels, and a reversal of contextual fear-conditioning deficits that are correlated with A␤ load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dosedependent changes in plasma A␤ levels, confirming pharmacodynamic activity of GSI-953 in humans.This research was supported by Wyeth Research. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABA receptors. Herein, we report new SAR insights in a series of 5β-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABA receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET).

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

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Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-R). Herein we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogues bearing a heterocyclic substituent at C-21. These efforts resulted in the identification of SGE-516, a balanced synaptic/extrasynaptic GABA(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators.

The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.

The pharmacological profile of WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino [6,7,1hi]indole], a novel 5-hydroxytryptamine (HT) 2C (serotonin) receptor-selective agonist is presented. WAY-163909 displaced [125 I]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT 2C receptor sites, in Chinese hamster ovary (CHO) cell membranes, with a K i value of 10.5 Ϯ 1.1 nM. Binding affinities determined for the human 5-HT 2A and 5-HT 2B receptor subtypes were 212 and 485 nM, respectively. In functional studies, WAY-163909 stimulated the mobilization of intracellular calcium in CHO cells stably expressing the human 5-HT 2C receptor with an EC 50 value of 8 nM, and E max relative to 5-HT of 90%. WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT 2A receptor subtype (EC 50 Ͼ Ͼ 10 M) and was a 5-HT 2B receptor partial agonist (EC 50 185 nM, E max 40%). WAY-163909 exhibited negligible affinity (Ͻ50% inhibition at 1 M) for other receptor sites examined, including human 5-HT 1A , D2, and D3 receptors, and the 5-HT transporter binding site in rat cortical membranes. WAY-163909 exhibited weak affinity for the human D4 (245 nM) and 5-HT 7 (343 nM) receptor subtypes and the ␣1 binding site in rat cortical membranes (665 nM). WAY-163909 produced a dose-dependent reduction in food intake in normal Sprague-Dawley rats (ED 50 ϭ 2.93 mg/kg), an effect blocked by a 5-HT 2C receptor antagonist but not by a 5-HT 2A or 5-HT 2B receptor antagonist. In addition, WAY-163909 decreased food intake in obese Zucker rats and diet-induced obese mice with ED 50 values of 1.4 and 5.19 mg/kg i.p., respectively, consistent with the potential utility of 5-HT 2C receptor agonists as antiobesity agents.At least 14 distinct 5-HT receptor subtypes have been cloned, and their classification has been based on both sequence similarity and common signal transduction pathways (for review, see Barnes and Sharp, 1999). The 5-HT 2 receptor subfamily currently accommodates three subtypes designated 5-HT 2A , 5-HT 2B , and 5-HT 2C , and these receptors belong to the large family of seven transmembrane domain G protein-coupled receptors. They display high sequence homology with each other and common signal transduction (Baxter et al., 1995), principally via the activation of phospholipase C. Alterations or dysfunction of the 5-HT 2C receptor has been implicated in a variety of conditions, including obesity, anxiety, depression, obsessive compulsive disorder, schizophrenia, migraine, and erectile dysfunction (Fozard and Gray, 1989;Kennett and Curzon, 1991;Sanders-Bush Article, publication date, and citation information can be found at