A novel, non-substrate-based series of glycine type 1 transporter inhibitors derived from high-throughput screening

Lowe, John; Drozda, Susan E.; Qian, Weimin; Peakman, Marie‐Claire; Liu, J.; Gibbs, John P.; Harms, John F.; Schmidt, Christopher J.; Fisher, Katherine; Strick, Christine A.; Schmidt, Anne W.; Vanase, M.; Lebel, Lorraine A.

doi:10.1016/j.bmcl.2006.12.109

Cited by 12 publications

(6 citation statements)

References 13 publications

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“…However, both compounds were halted at phase II for demonstrating little to no benefit over placebo. Nonsarcosine analogues have also been identified from [ 3 H]-glycine-based cellular uptake and competitive binding screens with radiolabeled GlyT1 ligand . Among them, bitopertin ( 33 ), identified by Roche, advanced to phase III clinical trials but failed to provide a significant effect over placebo in patients with suboptimally controlled positive symptoms.…”

Section: Small Molecule Slc Modulatorsmentioning

confidence: 99%

The Druggability of Solute Carriers

et al. 2019

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The transport of materials across membranes is a vital process for all aspects of cellular function, including growth, metabolism, and communication. Protein transporters are the molecular gates that control this movement and serve as key points of regulation for these processes, thus representing an attractive class of therapeutic targets. With more than 400 members, the solute carrier (SLC) membrane transport proteins are the largest family of transporters, yet, they are pharmacologically underexploited relative to other protein families and many of the available chemical tools possess suboptimal selectivity and efficacy. Fortuitously, there is increased interest in elucidating the physiological roles of SLCs as well as growing recognition of their therapeutic potential. This Perspective provides an overview of the SLC superfamily, including their biochemical and functional features, as well as their roles in various human diseases. In particular, we explore efforts and associated challenges toward drugging SLCs, as well as highlight opportunities for future drug discovery.

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Section: Small Molecule Slc Modulatorsmentioning

confidence: 99%

The Druggability of Solute Carriers

et al. 2019

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“…Consequently, intense effort is ongoing to understand the biochemical characteristics that enable substrates and inhibitors to bind to this polymorphic enzyme. Furthermore, [99] [99]…”

Section: Resultsmentioning

confidence: 99%

“…. Application of discrete structural modifications to control CYP2D6 inhibition[87][88][89][90][91][92][93][94][95][96][97][98][99][100][101].…”

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confidence: 99%

Medicinal Chemistry Strategies to Reduce CYP2D6 Inhibitory Activity of Lead Candidates

Bourdonnec¹,

Leister²

2009

CMC

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Among the various human cytochrome P450s (CYP450s) that catalyze the biotransformation of xenobiotics, CYP450 2D6 (CYP2D6) is one of the most important based on the number and wide variety of its drug substrates. CYP2D6 shows a high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences its expression and function. A number of drugs have been clinically implicated in major drug-drug interactions (DDI) via CYP2D6 inhibition. In order to avoid or minimize issues related to CYP2D6-mediated DDIs, pharmaceutical companies routinely screen for potential CYP2D6 liability of lead candidates in the early stage of the drug discovery process. This review summarizes the medicinal chemistry tactics employed to mitigate inhibitory activity at CYP2D6, identified through an extensive literature survey covering the 1998-2008 period.

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“…Compound 4 exhibited potent in vivo activity in the cerebral spinal fluid (CSF) glycine model, with excellent drug-like physical properties due to its lipophilicity, whereas compound 5 showed good selectivity and high affinity for the GlyT1 (K i (inhibitor constant) = 1.8 nM). 13,14 New classes of the 4H-1,2,4-triazole derivatives were reported selective GlyT1 inhibitors. 8 Compound 6 was moderately potent (half maximal inhibitory concentration (IC 50 ) = 64 nM) , had a good pharmacokinetics (PK) profile and was the most potent in the induced hyperlocomotion assay.…”

Section: Introductionmentioning

confidence: 99%