rg-1678 and Schizophrenia

Schizophrenia is a severe neuropsychiatric disorder without adequate current treatment. Recent theories of schizophrenia focus on disturbances of glutamatergic neurotransmission particularly at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors are regulated in vivo by the amino acids glycine and D-serine. Glycine levels, in turn, are regulated by glycine type I (GlyT1) transporters, which serve to maintain low subsaturating glycine levels in the vicinity of the NMDA receptor. A proposed approach to treatment of schizophrenia, therefore, is inhibition of GlyT1-mediated transport. Over the past decade, several well tolerated, high affinity GlyT1 inhibitors have been developed and shown to potentiate NMDA receptor-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GlyT1 inhibitor, and with the high affinity compound RG1678. Although definitive trials remain ongoing, encouraging results to date have been reported.

Topics: Animals; Glycine; Glycine Plasma Membrane Transport Proteins; Humans; Piperazines; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sulfones

RG1678 is a glycine transporter-1 inhibitor currently in Phase III trials for the treatment of the negative symptoms of schizophrenia and is being developed by Roche (in combination with Chugai). Recent Phase II data shows that RG1678 is effective in reducing the negative symptoms when given in combination with second generation antipsychotics.

Topics: Animals; Clinical Trials, Phase III as Topic; Glycine Plasma Membrane Transport Proteins; Humans; Neurosciences; Piperazines; Schizophrenia; Societies, Scientific; Sulfones

Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d-serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder.. Primary analysis was on MMN after double-blind crossover (60mg/kg/d, n=16, 6weeks) treatment with d-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120mg/kg/d, n=21) d-serine and bitopertin/placebo (10mg, n=29), a glycine transport inhibitor.. Double-blind d-serine treatment led to significant improvement in MMN frequency (p=0.001, d=2.3) generation and clinical symptoms (p=0.023, d=0.80). MMN frequency correlated significantly with change in symptoms (r=-0.63, p=0.002) following co-variation for treatment type. d-Serine treatment led to a significant, large effect size increase vs. placebo in evoked α-power in response to standards (p=0.036, d=0.81), appearing to normalize evoked α power relative to previous findings with controls. While similar results were seen with open-label d-serine, no significant effects of bitopertin were observed for symptoms or MMN.. These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia. Results overall support suggest that MMN may have negative, as well as positive, predictive value in predicting efficacy of novel compounds.. Clinicaltrials.gov: NCT00322023/NCT00817336 (d-serine); NCT01116830 (bitopertin).

Topics: Acoustic Stimulation; Adolescent; Adult; Antipsychotic Agents; Cognition Disorders; Contingent Negative Variation; Cross-Over Studies; Double-Blind Method; Evoked Potentials, Auditory; Female; Humans; Male; Meta-Analysis as Topic; Middle Aged; Piperazines; Schizophrenia; Serine; Sulfones; Time Factors; Young Adult

Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia and are associated with impaired generation of event-related potential measures including auditory mismatch negativity. Parallel studies of the NMDAR agonist D-serine have suggested that sensitivity of these measures to glutamate-based interventions is related to symptomatic and cognitive response. Bitopertin is a selective inhibitor of glycine transport. This study investigates effects of bitopertin on NMDAR-related event-related potential deficits in schizophrenia.. Patients with schizophrenia/schizoaffective disorder were treated with bitopertin (10 mg, n = 29), in a double-blind, parallel group investigation. Auditory mismatch negativity served as primary outcome measures. Secondary measures included clinical symptoms and neurocognitive performance.. No significant changes were seen with bitopertin for neurophysiological, clinical, or neurocognitive assessments.. These findings represent the first assessment of the effect of bitopertin on neurophysiological biomarkers. Bitopertin did not significantly affect either symptoms or NMDAR-related biomarkers at the dose tested (10 mg). Mismatch negativity showed high test-retest reliability, supporting its use as a target engagement measure.

Topics: Adult; Double-Blind Method; Female; Glycine Plasma Membrane Transport Proteins; Humans; Male; Middle Aged; Piperazines; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sulfones; Treatment Outcome

There is currently no standard of care for treatment of negative symptoms of schizophrenia, although some previous results with glutamatergic agonists have been promising.. Three (SunLyte [WN25308], DayLyte [WN25309], and FlashLyte [NN25310]) phase III, multicenter, randomized, 24-week, double-blind, parallel-group, placebo-controlled studies evaluated the efficacy and safety of adjunctive bitopertin in stable patients with persistent predominant negative symptoms of schizophrenia treated with antipsychotics. SunLyte met the prespecified criteria for lack of efficacy and was declared futile. Key inclusion criteria were age ≥18 years, DSM-IV-TR diagnosis of schizophrenia, score ≥40 on the sum of the 14 Positive and Negative Syndrome Scale negative symptoms and disorganized thought factors, unaltered antipsychotic treatment, and clinical stability. Following a 4-week prospective stabilization period, patients were randomly assigned 1:1:1 to bitopertin (5 mg and 10 mg [DayLyte] and 10 mg and 20 mg [FlashLyte]) or placebo once daily for 24 weeks. The primary efficacy end point was mean change from baseline in Positive and Negative Syndrome Scale negative symptom factor score at week 24.. The intent-to-treat population in DayLyte and FlashLyte included 605 and 594 patients, respectively. At week 24, mean change from baseline showed improvement in all treatment arms but no statistically significant separation from placebo in Positive and Negative Syndrome Scale negative symptom factor score and all other end points. Bitopertin was well tolerated.. These studies provide no evidence for superior efficacy of adjunctive bitopertin in any of the doses tested over placebo in patients with persistent predominant negative symptoms of schizophrenia.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Piperazines; Schizophrenia; Sulfones; Treatment Outcome; Young Adult

Symptoms of schizophrenia fall into three categories (positive, negative and cognitive symptoms), which probably impact differently on patient's health-related quality of life (HRQoL). The present study aimed to explore HRQoL in patients with prominent negative symptoms.. In the 323 patients with prominent negative symptoms included in a multicenter Phase II trial investigating the safety and efficacy of bitopertin, HRQoL was assessed using the Schizophrenia Quality of Life Scale (SQLS), symptoms severity using the Positive and Negative Syndrome Scale and functioning using the Personal and Social Performance Scale. SQLS measurement properties were assessed; HRQoL was compared between treatment arms, and relationships between HRQoL, symptoms and functioning at baseline were explored.. Both SQLS scores (Vitality/Cognition and Psychosocial Feelings) demonstrated good test-retest (ICC = 0.77 and 0.74) and internal consistency reliability (Cronbach's α = 0.86 and 0.93). Clinical validity with regard to schizophrenia severity and ability to detect change in severity of symptoms of schizophrenia were satisfactory. The SQLS structure was not formally disconfirmed. No statistically significant difference was observed between treatment arms. Negative symptoms were more strongly associated with functioning than positive symptoms. Functioning and Anxiety/Depression were strongly related to both SQLS domains.. Overall, SQLS measurement properties were supported in these patients with prominent negative symptoms of schizophrenia. The impact of negative symptoms on functioning and HRQoL suggests that improving these symptoms will be a meaningful benefit in this population of patients.

Topics: Adult; Female; Health Status; Humans; Male; Middle Aged; Piperazines; Quality of Life; Reproducibility of Results; Schizophrenia; Sulfones; Surveys and Questionnaires

Bitopertin, a glycine reuptake inhibitor, was investigated as a novel treatment for schizophrenia. We report all the results of a double-blind randomized study assessing safety and efficacy following 52-week adjunctive treatment with bitopertin in Japanese patients with schizophrenia.. This study enrolled Japanese outpatients with schizophrenia who met criteria for either "negative symptoms", i.e., patients with persistent, predominant negative symptoms of schizophrenia even after long-term treatment with antipsychotics or "sub-optimally controlled symptoms", i.e., patients with insufficiently improved symptoms of schizophrenia even after long-term treatment with antipsychotics, respectively. One hundred sixty-one patients were randomly assigned to receive 52-week treatments with bitopertin doses of 5, 10, or 20 mg/day at ratio of 1:5:5, where existing antipsychotics were concomitantly administered. Efficacy endpoints included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI), and Personal and Social Performance (PSP). The purpose of the present study is primarily to evaluate the safety, and secondarily to investigate the clinical efficacy of bitopertin.. One hundred fourteen patients (71 %) completed 52-week treatment with bitopertin. Most of the adverse events were mild or moderate in their severity. The patients in the 20-mg group experienced more adverse events than the patients in the other two groups. Common dose-dependent adverse events were somnolence and insomnia associated with worsening schizophrenia. The blood hemoglobin levels gradually decreased from baseline in a dose-dependent manner, but there were no patients with the decrease below 10 g/dL that would have led to their discontinuation. All the efficacy endpoints gradually improved in all the treatment groups for both of the two symptoms, while there were no clear differences among the three dose groups.. Altogether, bitopertin was found to be generally safe and well-tolerated for the treatment of patients with schizophrenia. All three bitopertin treated groups showed improvements in all the efficacy endpoints for both of the two symptoms, i.e., "negative symptoms" and "sub-optimally controlled symptoms", throughout the duration of the study.. Japan Pharmaceutical Information Center, number JapicCTI-111627 (registered on September 20, 2011).

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Japan; Male; Middle Aged; Piperazines; Schizophrenia; Sulfones; Treatment Outcome

Many patients with schizophrenia require high doses of medication for their ongoing psychotic symptoms. Glutamate theories and findings from studies showing efficacy of sarcosine, an endogenous, non-selective glycine-reuptake inhibitor mediated by GlyT1, offer an alternative approach. We undertook the SearchLyte trial programme to examine the efficacy of bitopertin, a selective GlyT1-mediated glycine-reuptake inhibitor, as an adjunctive treatment to ongoing antipsychotic treatment.. SearchLyte consisted of three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies done in outpatient clinics in Asia, Europe, and North and South America (TwiLyte done at 109 sites, NightLyte at 84, and MoonLyte at 87). Participants were male and female outpatients, aged at least 18 years, meeting DSM-IV criteria for schizophrenia with suboptimally controlled positive symptoms despite treatment with antipsychotics. Inclusion criteria included a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and antipsychotic treatment stability for the past 12 weeks before randomisation. Key exclusion criteria included meeting criteria for symptomatic remission or previous treatment with a GlyT1 inhibitor or any other investigational drug. After a screening or 4-week prospective stabilisation period, we randomly assigned participants (1:1:1) to a 12-week, double-blind treatment of either placebo or one of two fixed doses of oral, once-daily bitopertin (10 or 20 mg in TwiLyte and NightLyte; 5 or 10 mg in MoonLyte) added to their current antipsychotic medicine. After completion of 12 weeks' treatment, the study design allowed for additional double-blind treatment for 40 weeks to assess maintenance of the effect, followed by a randomised 4-week washout period to assess withdrawal effects. Subsequently, all patients were offered the opportunity to receive bitopertin treatment in a 3-year follow-up. The primary efficacy endpoint was the mean change from baseline in the PANSS Positive Symptom Factor Score (PSFS) at week 12, analysed in the modified intention-to-treat population. The trials were registered at ClinicalTrials.gov (numbers NCT01235520 [TwiLyte], NCT01235585 [MoonLyte], and NCT01235559 [NightLyte]).. Between Nov 19, 2010, and Dec 12, 2014, we randomly assigned 1794 patients to treatment, of whom 1772 were treated and analysed. MoonLyte was discontinued in September, 2014, on the basis of results from futility analyses. Across studies and treatment arms, most patients completed 12 weeks of treatment (505 in TwiLyte, 517 in NightLyte, and 506 in MoonLyte). Only one study, NightLyte, met the primary endpoint where the PANSS PSFS significantly differed from placebo at week 12, and only in the 10-mg arm: mean difference in score -1·37, 95% CI -2·27 to -0·47; p=0·0028. Improvements from baseline for the bitopertin 20-mg arm in Nightlyte were not significant compared with placebo: -3·77, 95% CI -4·40 to -3·14; p=0·3142. Results from the other two studies also did not differ from placebo (TwiLyte 0·58, 95% CI -0·34 to 1·50, p=0·22 for 10 mg and 0·43, -0·49 to 1·36, p=0·36 for 20 mg; MoonLyte 0·06, 95% CI -0·79 to 0·92, p=0·88 for 5 mg and 0·44, -0·41 to 1·28, p=0·31 for 10 mg). Placebo responses varied across studies and might have contributed to the differences in efficacy between studies. Four deaths occurred during the 12-week treatment period, three in NightLyte (upper gastrointestinal haemorrhage, alcohol poisoning and related head injury, and a completed suicide) and one in MoonLyte (myocardial infarction in a patient with pre-existing risk factors). Only the death by suicide was deemed related to the study drug. The incidence of serious adverse events was low across treatment groups in all three studies; psychiatric disorders were the most frequently reported serious adverse events and the most frequent cause of adverse events leading to discontinuation.. Only one of six active treatment arms across the three studies offered an advantage of adjunctive bitopertin over placebo for the treatment of suboptimally controlled symptoms of schizophrenia. The small improvement associated with bitopertin together with the varying placebo response suggests that adjunctive bitopertin treatment might offer only modest benefit to suboptimal responders to antipsychotics, if any.. F Hoffmann-La Roche.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Schizophrenia; Sulfones; Treatment Outcome

In schizophrenia, the severity of negative symptoms is a key predictor of long-term disability. Deficient signaling through the N-methyl-D-aspartate receptor is hypothesized to underlie many signs and symptoms associated with schizophrenia in particular negative symptoms. Glycine acts as an N-methyl-D-aspartate receptor coagonist. Blockade of the glycine transporter type 1 to inhibit glycine reuptake and elevate synaptic glycine concentrations represents an effective strategy to enhance N-methyl-D-aspartate receptor transmission.. To determine the efficacy and safety of bitopertin (RG1678), a glycine reuptake inhibitor, in patients with schizophrenia and predominant negative symptoms who were stable while taking an antipsychotic treatment.. This randomized, double-blind, placebo-controlled, phase 2 proof-of-concept trial involved 323 patients with schizophrenia and predominant negative symptoms across 66 sites worldwide.. Bitopertin (10, 30, or 60 mg/d) or placebo added to standard antipsychotic therapy for a treatment duration of 8 weeks.. Change from baseline in the Positive and Negative Syndrome Scale negative factor score.. In the per-protocol population, 8 weeks of treatment with bitopertin was associated with a significant reduction of negative symptoms in the 10-mg/d (mean [SE] reduction in negative symptoms score, -25% [2%]; P = .049) and 30-mg/d (mean [SE], -25% [2%]; P = .03) bitopertin groups, a significantly higher response rate and a trend toward improved functioning in the 10-mg/d group when compared with placebo (mean [SE], -19% [2%]). Results reached trend-level significance in the intent-to-treat population. Estimates of bitopertin binding to glycine transporter type 1 showed that low to medium levels of occupancy yielded optimal efficacy in patients, consistent with findings in preclinical assays.. Bitopertin-mediated glycine reuptake inhibition may represent a novel treatment option for schizophrenia, with the potential to address negative symptoms.. clinicaltrials.gov Identifier: NCT00616798.

Topics: Adult; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glycine Plasma Membrane Transport Proteins; Humans; Male; Piperazines; Schizophrenia; Schizophrenic Psychology; Sulfones; Treatment Outcome

Bitopertin is a glycine reuptake inhibitor postulated to improve N-methyl-d-aspartate receptor hypofunction by increasing synaptic glycine concentrations. This randomised, double-blind, placebo- and active-controlled phase II/III trial evaluated the efficacy and safety of bitopertin monotherapy over 4 weeks in patients with acute exacerbation of schizophrenia. Of 301 patients randomised, 299 received placebo (n=80), bitopertin 10mg (n=80) or 30mg (n=77), or olanzapine 15mg (n=62). The primary endpoint, change from baseline in mean Positive and Negative Syndrome Scale (PANSS) total score, showed non-statistically significant improvements with bitopertin 30mg and olanzapine vs. placebo: bitopertin 10mg (-11.7; standard error [SE], 1.89; p=0.945), bitopertin 30mg (-15.3; SE, 1.87; p=0.211), olanzapine (-14.9; SE, 2.13; p=0.295) and placebo (-11.9; SE, 1.90). The PANSS positive subscale score, a secondary endpoint, also showed improvement with bitopertin 30mg (p=0.030) whereas a trend was observed with olanzapine (p=0.072) vs. placebo. Although not statistically significant, bitopertin 30mg and olanzapine reduced overall illness severity (Clinical Global Impression-Severity Scale; p=0.098 and p=0.126, respectively). More patients receiving bitopertin 30mg (51.3%) or olanzapine (52.5%) than placebo (32.9%) were ready for hospital discharge at Week 4 (bitopertin, p=0.014; olanzapine, p=0.024). In summary, this study failed due to lack of statistical separation of either bitopertin or olanzapine (active control) from placebo on the primary endpoint. Of interest, improved positive symptoms and readiness for hospital discharge were associated with both bitopertin and olanzapine treatment. Bitopertin was safe and well tolerated in this study.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Piperazines; Schizophrenia; Sulfones; Treatment Outcome

The PANSS is a valid instrument assessing schizophrenia symptom severity. Analyses have identified a five-factor solution. The negative symptom factor (NSFS) is robust, having been replicated in multiple analyses. The score has superior content validity versus the negative subscale. Aspects of validity in patients with predominant negative symptoms have yet to be established. The present data are from a Phase IIb study of add-on bitopertin therapy in schizophrenia outpatients with prominent negative or disorganized thought symptoms treated with antipsychotics. Analyses were conducted to evaluate reliability, validity and sensitivity to change. Test-retest screening to baseline was high (ICC=0.93). This was maintained in-study, for patients with no change in CGI negative symptom severity (CGI-S-N). Internal consistency at baseline was adequate (α=0.71) and increased at later assessments. Pearson correlation at baseline showed a good association between NSFS and CGI-S-N (0.63), but not overall CGI-S (0.31). Association with PSP at baseline was moderate (-0.39) and for change at Week eight good (-0.65). NSFS responders (≥20% improvement) at Week eight showed a significant improvement in function. The analyses demonstrated reliability, validity and ability to detect change of the NSFS, in schizophrenia patients with prominent negative or disorganized thought symptoms.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Outpatients; Piperazines; Psychiatric Status Rating Scales; Reproducibility of Results; Schizophrenia; Sulfones; Symptom Assessment; Treatment Outcome

Topics: Animals; Cell Line; Dose-Response Relationship, Drug; Drug Discovery; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Molecular Structure; Nerve Tissue Proteins; Receptors, G-Protein-Coupled; Schizophrenia; Structure-Activity Relationship

Glycine transporter-1 (GlyT1) inhibition has been extensively studied both in pharmaceutical companies and academic institutions primarily as a potential new approach to treat schizophrenia, a severe and chronic mental illness. More recently, preclinical results have suggested that this approach could also have therapeutic potential for CNS disorders beyond schizophrenia as well as for non-CNS indications. Over the past 17 years, Roche has been a key player in the GlyT1 field with the discovery and development of bitopertin, the most advanced GlyT1 inhibitor to date and the only one which completed Phase III clinical studies for schizophrenia. In this article, we relate the eventful journey of the discovery and development of bitopertin, from project initiation in 2001 to its evaluation today in patients suffering from beta-thalassemia, a monogenic hereditary haematological disorder.

Topics: Animals; beta-Thalassemia; Drug Development; Drug Discovery; Glycine Plasma Membrane Transport Proteins; High-Throughput Screening Assays; Humans; Piperazines; Schizophrenia; Sulfones

Topics: Humans; Memory; N-Methylaspartate; Piperazines; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sulfones

Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1).. The primary objective of these studies was to explore the relationship between plasma exposure and glycine cerebrospinal fluid (CSF) concentrations following administration of bitopertin and RG7118 in healthy volunteers.. The bitopertin study comprised four dose levels (3, 10, 30 and 60 mg) administered once daily for 10 days. In the RG7118 study, placebo, 15 or 30 mg RG7118 was administered once daily for 28 days. CSF samples were taken on day -2 and day 10, and day -1 and day 26 for bitopertin and RG7118, respectively.. Twenty-two and 24 subjects participated in the bitopertin and RG7118 study, respectively. In the bitopertin study, CSF glycine concentrations showed a dose-dependent increase from baseline to day 10. The geometric mean ratios (coefficient of variation) of AUC0-12 h on day 10 over baseline were 1.3 (17 %), 1.3 (49 %), 1.7 (18 %) and 2.3 (14 %) after 3, 10, 30 and 60 mg, respectively. In the RG7118 study, the geometric mean ratio of glycine concentration (CV) on day 26 at 6 h post-dose over time-matched baseline was approx. 1.9 (24 and 15 %) for 15 and 30 mg.. The mechanism of action of bitopertin and RG7118, i.e. inhibition of glycine reuptake in the brain, was confirmed. The maximal increase observed in healthy volunteers was similar to the one observed in animals showing the good translatability of this biomarker.

Topics: Adult; Area Under Curve; Brain; Glycine; Glycine Plasma Membrane Transport Proteins; Healthy Volunteers; Humans; Imidazoles; Male; Neurotransmitter Uptake Inhibitors; Piperazines; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sulfones; Synaptic Transmission

Topics: Antipsychotic Agents; Double-Blind Method; Humans; Piperazines; Schizophrenia; Sulfones

Topics: Antipsychotic Agents; Clinical Trials, Phase II as Topic; Glycine Plasma Membrane Transport Proteins; Humans; Piperazines; Schizophrenia; Schizophrenic Psychology; Sulfones; Treatment Outcome

Topics: Affect; alpha7 Nicotinic Acetylcholine Receptor; Antipsychotic Agents; Controlled Clinical Trials as Topic; Electric Stimulation Therapy; Glutamic Acid; Glycine; Glycine Plasma Membrane Transport Proteins; Happiness; Humans; Piperazines; Pleasure; Risperidone; Schizophrenia; Schizophrenic Psychology; Sulfones; Treatment Failure

Topics: Antipsychotic Agents; Female; Glycine Plasma Membrane Transport Proteins; Humans; Male; Piperazines; Schizophrenia; Schizophrenic Psychology; Sulfones

The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.

Topics: Animals; Brain; CHO Cells; Cricetinae; Cricetulus; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Glycine Plasma Membrane Transport Proteins; Humans; Macaca fascicularis; Male; Mice; Microdialysis; Motor Activity; Patch-Clamp Techniques; Piperazines; Psychotropic Drugs; Rats; Rats, Sprague-Dawley; Schizophrenia; Stereoisomerism; Structure-Activity Relationship; Sulfones