2-(Pyrrolidin-1-yl)ethyl-3,4-dihydroisoquinolin-1(<i>2H</i>)-one Derivatives as Potent and Selective Histamine-3 Receptor Antagonists

On the basis of the previously reported benzimidazole 1,3′-bipyrrolidine benzamides (<b>1</b>), a new class of 2-(pyrrolidin-1-yl)­ethyl-3,4-dihydroisoquinolin-1­(2<i>H</i>)-one derivatives (<b>3</b>–<b>50</b>) were synthesized and evaluated as potent H₃ receptor antagonists. In particular, compound <b>39</b> exhibited potent in vitro binding and functional activities at the H₃ receptor, good selectivities against other neurotransmitter receptors and ion channels, acceptable pharmacokinetic properties, and a favorable in vivo profile

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

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)