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)

Discovery of Disubstituted Imidazo[4,5‑<i>b</i>]pyridines and Purines as Potent TrkA Inhibitors

Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (<b>1a</b>) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo­[4,5-<i>b</i>]­pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds <b>2d</b> and <b>3a</b>