ABSTRACT
Endogenous and synthetic neuroactive steroids (NASs) or neurosteroids are effective modulators of multiple signaling pathways including receptors for the γ-aminobutyric acid A (GABAA) and glutamate, in particular N-methyl-d-aspartate (NMDA). These receptors are the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS), and there is growing evidence suggesting that dysregulation of neurosteroid production plays a role in numerous neurological disorders. The significant unmet medical need for treatment of CNS disorders has increased the interest for these types of compounds. In this review, we highlight recent progress in the clinical development of NAS drug candidates, in addition to preclinical breakthroughs in the identification of novel NASs, mainly for GABAA and NMDA receptor modulation.
Subject(s)
Central Nervous System Diseases/drug therapy , Drug Discovery , Neurotransmitter Agents/pharmacology , Receptors, GABA-A/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Central Nervous System Diseases/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Conformation , Neurotransmitter Agents/chemistry , Structure-Activity RelationshipABSTRACT
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).
Subject(s)
Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Triazines/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Dizocilpine Maleate/antagonists & inhibitors , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Drug , Humans , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Models, Molecular , Molecular Structure , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/chemistry , Rats , Structure-Activity Relationship , Triazines/administration & dosage , Triazines/chemistryABSTRACT
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.
Subject(s)
Central Nervous System Diseases , Cognitive Dysfunction , Neurosteroids , Allosteric Regulation , Cognitive Dysfunction/drug therapy , Humans , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
The 5-hydroxytryptamine 2C (5-HT(2C)) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT(2C) receptor-selective agonist vabicaserin [(-)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT(2B) receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced (125)I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT(2C) receptor sites in Chinese hamster ovary cell membranes with a K(i) value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT(2B) receptor subtype using [(3)H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC(50), 8 nM; E(max), 100%) in stimulating 5-HT(2C) receptor-coupled calcium mobilization and exhibited 5-HT(2A) receptor antagonism and 5-HT(2B) antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT(2B) receptors, vabicaserin failed to induce a 5-HT(2B) receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT(2B) competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT(2B) receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT(2B) receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT(2B) receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT(2C) receptor agonist.
Subject(s)
Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Heterocyclic Compounds, 4 or More Rings/metabolism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Binding Sites/drug effects , CHO Cells , Cell Line , Cricetinae , Cricetulus , Humans , Male , Molecular Targeted Therapy , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Recombinant Proteins/metabolism , Serotonin/analogs & derivatives , Serotonin/metabolism , Serotonin 5-HT2 Receptor Antagonists/metabolism , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Signal Transduction/drug effectsABSTRACT
Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT(1A) receptor affinities. Their design, synthesis and structure-activity relationships are described.
Subject(s)
Benzofurans/chemistry , Benzofurans/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Protein Binding/physiology , Structure-Activity RelationshipABSTRACT
The structure-activity relationship (SAR) for three series of lactam-fused chroman derivatives possessing 3-amino substituents was evaluated. Many compounds exhibited affinities for both the 5-HT(1A) receptor and the 5-HT transporter. Compounds 45 and 53 demonstrated 5-HT(1A) antagonist activities in the in vitro cAMP turnover model.
Subject(s)
Chromans/chemistry , Lactams/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Serotonin Plasma Membrane Transport Proteins/metabolism , Chromans/chemical synthesis , Chromans/pharmacology , Cyclic AMP/metabolism , Drug Design , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT(6) receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT(6) binding affinity with K(i) values <10nM. Depending on substitution, both agonists (e.g., 6o: EC(50)=60nM, E(max)=70%) and antagonists (6y: IC(50)=17 nM, I(max)=86%) were identified in a 5-HT(6) adenylyl cyclase assay.
Subject(s)
Indoles/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistry , Sulfones/chemistry , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Ligands , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta 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 Abeta 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 gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-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 Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Sulfonamides/pharmacology , Thiophenes/pharmacology , Adolescent , Adult , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Binding, Competitive , CHO Cells , Cell Line , Cricetinae , Cricetulus , Dogs , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/toxicity , Fear/psychology , Female , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Rats , Rats, Sprague-Dawley , Receptors, Notch/physiology , Signal Transduction/drug effects , Sulfonamides/pharmacokinetics , Sulfonamides/toxicity , Thiophenes/pharmacokinetics , Thiophenes/toxicity , Young AdultABSTRACT
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.
Subject(s)
Pyridines/pharmacology , Pyrroles/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , HeLa Cells , Humans , Ligands , Pyridines/chemistry , Pyrroles/chemistry , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistryABSTRACT
Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Isoleucine/analogs & derivatives , Receptor, Notch1/metabolism , Alcohols , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Protein Precursor/chemistry , Animals , Drug Design , Humans , Isoleucine/chemistry , Models, Chemical , Propanolamines/chemistry , Sulfonamides/chemistryABSTRACT
A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.
Subject(s)
Cerebral Cortex/drug effects , Drinking Behavior/drug effects , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Animals , Cerebral Cortex/metabolism , Glutamic Acid/analysis , Glutamic Acid/metabolism , HeLa Cells , Humans , Protein Binding , Rats , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/chemical synthesis , gamma-Aminobutyric Acid/analysis , gamma-Aminobutyric Acid/metabolismABSTRACT
Cysteine-dependant aspartyl protease (caspase) activation has been implicated as a part of the signal transduction pathway leading to apoptosis. It has been postulated that caspase-3 inhibition could attenuate cell damage after an ischemic event and thereby providing for a novel neuroprotective treatment for stroke. As part of a program to develop a small molecule inhibitor of caspase-3, a novel series of 3,4-dihydropyrimido(1,2-a)indol-10(2H)-ones (pyrimidoindolones) was identified. The synthesis, biological evaluation and structure-activity relationships of the pyrimidoindolones are described.
Subject(s)
Caspase Inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Apoptosis/drug effects , Caspase 3/metabolism , Cell Line , Escherichia coli , Protease Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , Stroke/metabolism , Stroke/pathology , Structure-Activity RelationshipABSTRACT
gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Heterocyclic Compounds/chemical synthesis , Humans , Molecular Structure , Protein Binding , Receptors, Notch/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
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.
Subject(s)
Allosteric Regulation , Neurosteroids/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Age Factors , Animals , Cognition/drug effects , Hippocampus/drug effects , Hippocampus/physiology , Humans , Long-Term Potentiation/drug effects , Male , Methylation , Molecular Structure , Neurosteroids/chemistry , Neurosteroids/pharmacokinetics , Rats, Wistar , Structure-Activity RelationshipABSTRACT
5-Hydroxytryptamine (5-HT)(1A) receptors play an important role in multiple cognitive processes, and compelling evidence suggests that 5-HT(1A) antagonists can reverse cognitive impairment. We have examined the therapeutic potential of a potent (K(i) = 1.1 nM), selective (>100-fold), orally bioavailable, silent 5-HT(1A) receptor antagonist (K(B) = 1.3 nM) (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)-ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405). Oral administration of WAY-101405 was shown to be effective in multiple rodent models of learning and memory. In a novel object recognition paradigm, 1 mg/kg enhanced retention (memory) for previously learned information, and it was able to reverse the memory deficits induced by scopolamine. WAY-101405 (1 mg/kg) was also able to reverse scopolamine-induced deficits in a rat contextual fear conditioning model. In the Morris water maze, WAY-101405 (3 mg/kg) significantly improved learning in a paradigm of increasing task difficulty. In vivo microdialysis studies in the dorsal hippocampus of freely moving adult rats demonstrated that acute administration of WAY-101405 (10 mg/kg) increased extracellular acetylcholine levels. The selective radioligand [(3)H]WAY-100635, administered i.v., was used for in vivo receptor occupancy studies, where WAY-101405 occupied 5-HT(1A) receptors in the rat cortex, with an ED(50) value of 0.1 mg/kg p.o. Taken together, these studies demonstrate that WAY-101405 is a potent and selective, brain penetrant, orally bioavailable 5-HT(1A) receptor "silent" antagonist that is effective in preclinical memory paradigms at doses where approximately 90% of the postsynaptic 5-HT(1A) receptors are occupied. These results further support the rationale for use of this compound class in the treatment of cognitive dysfunction associated with psychiatric and neurological conditions.
Subject(s)
Aminopyridines/pharmacology , Cognition/drug effects , Cyclohexanes/pharmacology , Piperazines/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/pharmacology , Animals , Biological Availability , Brain/metabolism , Memory/drug effects , Models, Animal , Radioligand Assay , Rats , Serotonin Antagonists/administration & dosage , Serotonin Antagonists/pharmacokineticsABSTRACT
The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S(3) and S(1)(') substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Guanidine/pharmacology , Pyrroles/chemistry , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Enzyme Inhibitors/chemistry , Guanidine/chemistry , HumansABSTRACT
Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Combinatorial Chemistry Techniques , Guanidines/chemical synthesis , Guanidines/pharmacology , Pyrroles/chemistry , Crystallography, X-Ray , Guanidines/chemistry , Molecular Conformation , Molecular Structure , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
Using a cell-based assay, we have identified a new series of Notch-sparing gamma-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved gamma-secretase inhibitory potency and Notch-sparing selectivity.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Receptors, Notch/metabolism , Alzheimer Disease/drug therapy , Amyloid/chemistry , Amyloid Precursor Protein Secretases/chemistry , Carbon/chemistry , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Chemical , Receptors, Notch/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT(1A) receptor antagonists. The investigation of the structure-activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited equal binding affinities at 5-HT transporter (K(i)=4.9nM), 5-HT(1A) receptor (K(i)=6.2nM) and functioned as a 5-HT(1A) receptor antagonist.
Subject(s)
Antidepressive Agents/chemistry , Indoles/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Cyclohexylamines , Humans , Indoles/metabolism , Indoles/pharmacology , Piperazines , Serotonin 5-HT1 Receptor Antagonists , Structure-Activity RelationshipABSTRACT
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).