Discovery of GlyT1 inhibitors with improved pharmacokinetic properties

Wolkenberg, S. E.; Zhao, Zhijian; Wisnoski, David D.; Leister, William; O’Brien, Julie A.; Lemaire, Wei; Williams, David L.; Jacobson, Marlene A.; Sur, Cyrille; Kinney, Gene G.; Pettibone, D. J.; Tiller, Philip R.; Smith, Sheri; Gibson, Christopher R; Bennett, K; Polsky-Fisher, Stacey L.; Lindsley, Craig W.; Hartman, George D.

doi:10.1016/j.bmcl.2009.01.015

Cited by 22 publications

(20 citation statements)

References 16 publications

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“…As M22 exhibits excellent pharmacokinetic features, 22) our results suggested that this compound is a promising candidate for use as an anti-epilepsy drug.…”

Section: Discussionmentioning

confidence: 59%

“…1), which has been reported as a potential GlyT1 inhibitor in the development of anti-schizophrenia drugs and which exhibits excellent pharmacokinetic properties (Oral bioavailability 38%, t 1/2 : 11.8 h), [22][23][24] was evaluated for GlyT1 inhibition and anti-seizure activity in a mouse model. Our results showed that M22 elevated the seizure threshold in the MEST test and did not impair locomotion or motor coordination in mice.…”

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confidence: 99%

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A Highly Selective Inhibitor of Glycine Transporter-1 Elevates the Threshold for Maximal Electroshock-Induced Tonic Seizure in Mice

Zhao

Tao

Xian

et al. 2016

Biological & Pharmaceutical Bulletin

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Many anti-epileptic drugs (AEDs) that mainly target ion channels or post-synaptic receptors are in clinical use, but a proportion of patients are resistant to these traditional AEDs and experience repeated severe break-out seizures. Given its involvement in the etiology of epilepsy, the neurotransmitter glycine may serve as a novel target for epilepsy treatment. Increasing evidence suggests that inhibitors of glycine transporter 1 (GlyT1) exhibit anti-seizure properties in mouse models and show potential as anti-convulsions drugs. In the present study, we investigated the effect of a highly selective GlyT1 inhibitor (named M22) on glycine transport kinetics using a radioactive substrate uptake assay and investigated the anti-seizure effects of M22 on the maximal electroshock seizure threshold (MEST) test and the timed intravenous (i.v.) pentylenetetrazole (PTZ) intravenous test. Our results demonstrate that M22 was capable of elevating the seizure threshold in the MEST test but did not alter the seizure threshold in the PTZ i.v. test. Strychnine, an inhibitor of glycine receptor activity, reversed the threshold elevation at a subconvulsive dosage (0.1 mg/kg subcutaneously) in the MEST test and did not affect M22 plasma levels in mice, suggesting that the anti-seizure effect in this model may be mediated by increased glycine receptor activity. Moreover, M22 administration did not influence motor function and coordination in mice. In combination with the previously reported excellent pharmacokinetic features of M22, our present results suggested that M22 has the potential to serve as a new anticonvulsive drug or as a lead compound for the development of AEDs.

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“…As M22 exhibits excellent pharmacokinetic features, 22) our results suggested that this compound is a promising candidate for use as an anti-epilepsy drug.…”

Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 99%

A Highly Selective Inhibitor of Glycine Transporter-1 Elevates the Threshold for Maximal Electroshock-Induced Tonic Seizure in Mice

Zhao

Tao

Xian

et al. 2016

Biological & Pharmaceutical Bulletin

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“…Recent publications suggest that a great deal of pharmaceutical industry and academic interest exists in the identification and development of selective GlyT1 inhibitors for the treatment of the cognitive and negative symptoms of schizophrenia by modulating the NMDA receptor (the so-called NMDA receptor hypofunction hypothesis of schizophrenia) [15][16][17][18][19][20][21][22][23][24][25][26][41][42][43][44][45][46][47][48][49][50]. These efforts have led to the development of numerous and structurally diverse GlyT1 inhibitors that are classified as sarcosine and nonsarcosine based; moreover, many have been in the clinic, and efficacy has been demonstrated [15][16][17][18][19][20][21][22][23][24][25][26][41][42][43][44][45][46][47][48][49][50].…”

Section: Scaffold Hopping To Access Novel Glycine Transporter Type 1 mentioning

confidence: 99%

“…These efforts have led to the development of numerous and structurally diverse GlyT1 inhibitors that are classified as sarcosine and nonsarcosine based; moreover, many have been in the clinic, and efficacy has been demonstrated [15][16][17][18][19][20][21][22][23][24][25][26][41][42][43][44][45][46][47][48][49][50]. As with the T-type calcium channel antagonists, the IP space is highly congested, and once again, Merck published and patented a number of variants with a central 4,4-disubstituted piperidine core -an ideal scaffold form to scaffold hop [38,[42][43][44][45][46][47][48][49][50].…”

Section: Scaffold Hopping To Access Novel Glycine Transporter Type 1 mentioning

confidence: 99%

“…Merck's effort began with an HTS effort that identified 21 [23], which evolved into related congeners 22-24 [24][25][26] and ultimately the clinical candidate 25, MK-2637 (Figure 16.7) [51]. Here, we employed the same scaffold hopping strategies described previously, and were rapidly able to develop four patented series of GlyT1 inhibitors, represented by 26-28 (Figure 16.8) [15][16][17][18][19][20].…”

Section: Scaffold Hopping To Access Novel Glycine Transporter Type 1 mentioning

confidence: 99%

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