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GlyT-1 Inhibitors: From Hits to Clinical Candidates

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Small Molecule Therapeutics for Schizophrenia

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 13))

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Abstract

The treatment of schizophrenia has long been dominated by aminergic receptor antagonist-based therapeutics largely founded on the dopamine hypothesis of schizophrenia. More recently the glutamatergic theory has come to the fore which may potentially address some of the deficiencies of current therapies. While there are many approaches to manipulating the glutamatergic system, the most advanced approach is to increase synaptic concentrations of the NMDA receptor co-agonist glycine via inhibition of the glycine transporter 1 (GlyT-1). Here we will describe the background biological rationale for this approach and review the diverse classes of compounds which have been identified as GlyT-1 inhibitors with particular focus on the identification of those molecules which have entered the clinical stages of development. The role of target kinetics in drug action, a review of the rich vein of PET ligand development and their use in clinical development and the status of clinical-stage compounds will be addressed. Finally there is a discussion of some of the issues that have arisen with the discovery and development of GlyT-1 inhibitors and the prospects for the future of this mechanistic approach.

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Abbreviations

ADMET:

Adsorption, distribution, metabolism, excretion, toxicity

ASST:

Attentional set-shifting task in rats

CADSS:

Clinician administered dissociative symptoms scale

CAR:

Conditioned avoidance response

CBT:

Cognitive-behavioural therapy

CSF:

Cerebrospinal fluid

DAAO:

d-Amino acid oxidase

DAT:

Dopamine transporter

EEG:

Electroencephalogram

EPSCs:

Excitatory postsynaptic currents

ErbB4:

Receptor tyrosine-protein kinase erbB-4

Gly:

Glycine

GlyB:

Strychnine-insensitive glycine-B subunit

GlyR:

Glycine receptor

GlyT-1:

Glycine transporter-1

GlyT-2:

Glycine transporter-2

h:

Hour(s)

hERG:

Human ether-à-go-go-related gene

HTS:

High-throughput screening

i.v.:

Intravenous

kg:

Kilogram

LeuT:

Leucine transporter

LeuTAa:

Leucine transporter from Aquifex aeolicus

LTP:

Long-term potentiation

mPFC:

Medial prefrontal cortex

MED:

Minimum effective dose

MEST:

Maximal electroshock test

NMDA:

N-Methyl-d-aspartic acid

NR1:

NMDA receptor subunit-1

NRG-1:

Neuregulin receptor 1

ORD:

Object retrieval–detour

p.o.:

Per os

PANNS:

Positive and negative syndrome scale

PCP:

Phencyclidine

PDSS:

Panic Disorder Severity Scale

PET:

Positron emission tomography

PFC:

Prefrontal cortex

P-gp:

P-glycoprotein

PK:

Pharmacokinetics

PPB:

Plasma protein binding

s.c.:

Subcutaneous

SAR:

Structure activity relationship

SSRI:

Selective serotonin reuptake inhibitor

SRR:

Serine racemase

TCA:

Tricyclic antidepressant

TM:

Transmembrane helix

WT:

Wild type

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  1. Rod Porter Consultancy, Ashwell, Herts, UK

    Roderick A. Porter

  2. Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, UK

    Lee A. Dawson

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    Sylvain Celanire

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    Sonia Poli

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Porter, R.A., Dawson, L.A. (2014). GlyT-1 Inhibitors: From Hits to Clinical Candidates. In: Celanire, S., Poli, S. (eds) Small Molecule Therapeutics for Schizophrenia. Topics in Medicinal Chemistry, vol 13. Springer, Cham. https://doi.org/10.1007/7355_2014_53

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