Identification of an Orally Bioavailable, Potent, and Selective Inhibitor of GlyT1

Blackaby, Wesley P.; Lewis, Richard T.; Thomson, Joanne L.; Jennings, Andrew S. R.; Goodacre, Simon; Street, Leslie J.; MacLeod, Angus M.; Pike, Andrew; Wood, Suzanne; Thomas, Steve; Brown, Terry; Smith, Alison J.; Pillai, Gopalan V.; Almond, Sarah; Guscott, Martin R.; Burns, H. Donald; Eng, Wai-si; Ryan, Christine; Cook, Jacquelynn J.; Hamill, Terence G.

doi:10.1021/ml1001085

Cited by 19 publications

(14 citation statements)

References 23 publications

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“…130 Therefore, GlyT1 inhibitors would be predicted to control synaptic glycine concentrations and to potentiate NMDA receptor function in vivo to ameliorate the negative symptoms of schizophrenia. 131 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 35 moiety yielded 99 (DCCCyB), 132 with a marginal increase in potency. However, this molecular modification significantly improved human and rat liver microsomal turnover compared to 98 as shown in Figure 43.…”

Section: Compounds 91 (Naltrexone/vivitrol) and 92 (Nalmefene/revex):mentioning

confidence: 99%

“…However, this molecular modification significantly improved human and rat liver microsomal turnover compared to 98 as shown in Figure 43. 132 Compound 99 has a good PK profile in animal models. Furthermore, it is not a substrate of P-gp, and thus achieves a high brain to plasma ratio of 2.3, and is efficacious in various rodent models.…”

Section: Compounds 91 (Naltrexone/vivitrol) and 92 (Nalmefene/revex):mentioning

confidence: 99%

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The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

2016

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Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,

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Section: Compounds 91 (Naltrexone/vivitrol) and 92 (Nalmefene/revex):mentioning

confidence: 99%

Section: Compounds 91 (Naltrexone/vivitrol) and 92 (Nalmefene/revex):mentioning

confidence: 99%

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

2016

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“…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%

“…All four cases withstood patent examination, and the US patents are beginning to issue [15,16]. Similar to the T-type calcium antagonists described earlier, these series displayed enantiospecific activity [15][16][17][18][19][20] and provided rapid access to potent GlyT1 inhibitors with comparable potency (IC 50 values from 750 pM to 300 nM), selectivity, DMPK profiles, and pharmacodynamics profiles to those developed by Merck [23][24][25][26]51]. Clear themes emerged as bioisosteric replacements for the piperidine core, and solid IP resulted once again.…”

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

confidence: 99%

Case Study 1: Scaffold Hopping for T‐Type Calcium Channel and Glycine Transporter Type 1 Inhibitors

Konkol

Senter

Lindsley

2013

Methods and Principles in Medicinal Chemistry

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“…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.…”

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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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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Identification of an Orally Bioavailable, Potent, and Selective Inhibitor of GlyT1

Cited by 19 publications

References 23 publications

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

Case Study 1: Scaffold Hopping for T‐Type Calcium Channel and Glycine Transporter Type 1 Inhibitors

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

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