Synthesis and Biological Evaluation ofN-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1

Abstract

Abstract:We previously disclosed the discovery of rationally designed N- ((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine

Process-Divergent Syntheses of 4- and 5-Sulfur-Functionalized 1,2,3-Triazoles via Copper-Catalyzed Azide–Alkyne Cycloadditions of 1-Phosphinyl-2-sulfanylethynes

“…13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 140.4, 138.1 (q, J = 1.0 Hz), 137.2, 131.1, 131.1 (q, J = 32.8 Hz), 129.92, 129.88, 128.2, 126.7, 126.1 (q, J = 4.0 Hz), 123.7 (q, J = 273.7 Hz), 53.6, 20.9. 19 7.28 (d, J = 7.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 5.82 (q, J = 8.0 Hz, 1H), 2.00 (d, J = 8.0 Hz, 3H). 13 General Procedure for the Synthesis of 7r−7ay.…”

“…13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 145. 7,135.0,133.0 (d,J = 109.2 Hz),132.1,131.8 (d,J = 10.1 Hz),130.8 (d,J = 101.1 Hz),129.6,129.0,128.9,128.8 (d,J = 10.1 Hz),128.4 (d,J = 13.1 Hz),127.1,126.3,125.1,124.9,122.3,51.2,21.6. 31 General Procedure for the Synthesis of Antagonists of the Pregnane X Receptor LC-58 and LC-59.…”

“…So far, many functionalized 1,2,3-triazoles have been synthesized to investigate their bioactive properties and apply them to medical treatments. Among them, 1,2,3-triazoles bearing sulfanyl and sulfonyl groups at the 4- and 5-positions exhibited significant biological activities such as antifungal A , antidepressant and selective serotonin reuptake inhibitor B , a drug for human sickle cell disease C , an inhibitor of glycine transporter-1 D , glucocorticoid receptor antagonist E , and antifungal against Trichosporon cutaneum F (Figure ).…”

Analysis of Binding Determinants for Different Classes of Competitive and Noncompetitive Inhibitors of Glycine Transporters

“…Bitopertin was finally found to have no significant therapeutic effect, while iclepertin is still on trial [ 22 ]. Compounds with a nonsarcosine structure, which include both competitive (most of the inhibitors) and noncompetitive (e.g., bitopertin and iclepertin) inhibitors, cause reversible inhibition [ 8 , 19 , 23 , 24 , 25 , 26 , 27 , 28 ]. Selective GlyT-2 inhibitors are limited in number and include compounds with an amino acid structure, of which the best known is ALX-1393, as well as those with a nonamino acid structure, such as ORG-25543 ( Figure 2 ) [ 29 , 30 , 31 ].…”

Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties

“…However, further investigation showed that many of these sarcosine derivatives produced a range of deleterious side effects including ataxia, lateral recumbency, and respiratory depression. , These side effects are likely the result of sustained elevation of glycine in caudal regions of the CNS, where GlyT1 and the glycine receptor (Gly A sites) are colocalized and play an important role in control of motor function and respiration. , More recent efforts to develop GlyT1 inhibitors have focused on non-sarcosine chemotypes. A significant number of these second-generation compounds, exemplified by compounds 3 – 7 , − have appeared in the literature recently, and some of these have demonstrated efficacy in preclinical animal models of cognition, pain, addiction, and anxiety. , In addition, several compounds have advanced into clinical development (including compounds 5 – 7 ), as potential treatments for the negative and cognitive symptoms associated with schizophrenia and as treatments for obsessive compulsive disorder (OCD), depression, addiction, and Parkinson’s disease. ,− To date, no GlyT1 inhibitors have received FDA approval.…”