Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano‑1<i>H</i>‑pyrazol-1′-yl)-19-nor-5β-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 GABA_A 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-1<i>H</i>-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217, <b>3</b>), a potent GABA_A receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound <b>3</b> 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

Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors

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 <b>1</b> and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of <b>1</b>, 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, <b>96</b>, displayed an IC₅₀ for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models