SAGE-718: A First-in-Class N-Methyl-d-Aspartate Receptor Positive Allosteric Modulator for the Potential Treatment of Cognitive Impairment.

N-Methyl-d-aspartate receptor (NMDAR) positive allosteric modulators (PAMs) have received increased interest as a powerful mechanism of action to provide relief as therapies for CNS disorders. Sage Therapeutics has previously published the discovery of endogenous neuroactive steroid 24(S)-hydroxycholesterol as an NMDAR PAM. In this article, we detail the discovery of development candidate SAGE-718 (5), a potent and high intrinsic activity NMDAR PAM with an optimized pharmacokinetic profile for oral dosing. Compound 5 has completed phase 1 single ascending dose and multiple ascending dose clinical trials and is currently undergoing phase 2 clinical trials for treatment of cognitive impairment in Huntington's disease.

Neuroactive Steroid N-Methyl-d-aspartate Receptor Positive Allosteric Modulators: Synthesis, SAR, and Pharmacological Activity.

Neuroactive steroids (NASs) play a pivotal role in maintaining homeostasis is the CNS. We have discovered that one NAS in particular, 24(S)-hydroxycholesterol (24(S)-HC), is a positive allosteric modulator (PAM) of NMDA receptors. Using 24(S)-HC as a chemical starting point, we have identified other NASs that have good in vitro potency and efficacy. Herein, we describe the structure activity relationship and pharmacokinetic optimization of this series that ultimately led to SGE-301 (42). We demonstrate that SGE-301 enhances long-term potentiation (LTP) in rat hippocampal slices and, in a dose-dependent manner, improves cognition in a rat social recognition study.

Polymer/glass hybrid DC-MZI thermal optical switch for 3D-integrated chips.

A directional coupler (DC) Mach-Zehnder interferometer (MZI) thermal optical switch based on a polymer and glass waveguide hybrid for three-dimensional (3D)-integrated chips is demonstrated. The proposed thermal optical switch consists of a polymer waveguide and glass waveguide prepared using an ion-exchange technique. The two waveguide cores can achieve coupling in the vertical direction, improving the integration level on 3D-integrated chips, realizing the complementary advantages of polymer and glass materials. Because of the opposite thermal optical coefficients of polymer and glass materials, and the good stability, low transmission loss and large thermal conductivity of glass material, the device with a low power consumption, small dimensions, fast response time and high extinction ratio can be easily obtained. The optical field coupling between the graded refractive index and step refractive index in 3D directions was simulated. The optimized coupling efficiency is 99.82% with an open-window dimension (w) of 3 µm. The refractive index difference between the diffusion surface center and cladding (Δn) is 0.022. The properties of the DC-MZI thermal optical switch were optimized, achieving a switch power consumption of 5.16 mW, a rising time of 128.8 µs, a falling time of 249.5 µs without an air trench structure, and a switch power consumption of 3.74 mW, a rising time of 140.7 µs, a falling time of 256.3 µs after the etching of an air trench structure with a heating electrode width of 8 µm.

TIPE2 expression is increased in peripheral blood mononuclear cells from patients with rheumatoid arthritis.

We investigated the changes in mRNA and protein expression of tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) and PEST-containing nuclear protein (PCNP) in peripheral blood lymphocytes from 54 patients with rheumatoid arthritis (RA) and the spleens of model mice with collagen-induced arthritis (CIA) to generate new ideas for clinical diagnosis and treatment. Expression levels of both TIPE2 and PCNP were higher in RA patients and CIA mice than in their respective controls. They were also higher in the 32 patients with active RA than in the 22 with inactive RA (P < 0.001 for both). After comprehensively treating patients with active RA with anti-inflammatory and antirheumatic drugs for 6 months, they were stable, and there was no difference in TIPE2 levels between the treated patients and those with inactive RA (P = 0.85). In addition, TIPE2 mRNA levels in peripheral blood correlated positively with PCNP (R2 = 0.744, P = 0.001). The DAS28 score correlated positively with peripheral blood TIPE2 levels in the RA patients (R2 = 0.945, P = 0.001). These findings suggest TIPE2 expression increases with the severity of RA.

Neuroactive Steroids. 2. 3α-Hydroxy-3ß-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5ß-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)A Receptor.

Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors. Herein, we report new SAR insights in a series of 5ß-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3ß-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5ß-pregnan-20-one (SAGE-217, 3), a potent GABAA 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).

Neuroactive Steroids. 1. Positive Allosteric Modulators of the (γ-Aminobutyric Acid)A Receptor: Structure-Activity Relationships of Heterocyclic Substitution at C-21.

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.