Optimisation of a series of potent, selective and orally bioavailable GlyT1 inhibitors

Thomson, Joanne L.; Blackaby, Wesley P.; Jennings, Andrew S. R.; Goodacre, Simon; Pike, Andrew; Thomas, Steve; Brown, Terry; Smith, Alison J.; Pillai, Gopalan V.; Street, Leslie J.; Lewis, Richard T.

doi:10.1016/j.bmcl.2009.02.102

Cited by 13 publications

(18 citation statements)

References 17 publications

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“…62 Another example of a compound containing a pyrazole was found in the work on glycine transporter 1 (GlyT1) inhibitors from Thomson and co-workers (Figure 28). 63 The pyrazole ring analogue 98 was replaced with a 1,2,3-triazole ring (99), which had little effect on improving dog liver microsomes (DLM) and HLM stability, but it had improved RLM stability. The improved RLM stability might be explained by the lower lipophilicity of analogue 99.…”

Section: ■ Heteroaromatic Compoundsmentioning

confidence: 99%

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Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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Section: ■ Heteroaromatic Compoundsmentioning

confidence: 99%

“…60 Figure 28. In vitro potency and LM data for selected GlyT1 receptor antagonists 63 (%TO = percent turnover). Figure 29.…”

Section: ■ Heteroaromatic Compoundsmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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“…17 Analysis of the plasma and brain drug levels required to achieve Occ 50 (1.2 and 0.2 μM, respectively) revealed a low brain to plasma ratio of 0.16. A similarly low brain to plasma ratio of 0.1 was determined from a 10 mg/kg oral dose of compound 3.…”

Section: -15mentioning

confidence: 99%

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

Blackaby

Lewis

Thomson

et al. 2010

ACS Med. Chem. Lett.

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“…12) Compound 4 13) has been also reported as the hybrid compound of 3a and Merck's sulfonamide derivatives. 14,15) Recently, our group discovered 5 (TP0439150), and reported its pharmacological profile. 16) Compound 5 shows potent in vitro GlyT1 inhibitory activity with an IC 50 value of 1.8 nM; oral dosing at 1 mg/kg elicited an increase in the concentration of glycine in the cerebrospinal fluid (CSF) in rats.…”

Section: Identification Of 1-methyl-n-(propan-2-yl)-n-({2-[4-(trifluomentioning

confidence: 99%

Identification of 1-Methyl-N-(propan-2-yl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1H-imidazole-4-carboxamide as a Potent and Orally Available Glycine Transporter 1 Inhibitor

Yamamoto

Ohta

Abe

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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Optimisation of a series of potent, selective and orally bioavailable GlyT1 inhibitors

Cited by 13 publications

References 17 publications

Mitigating Heterocycle Metabolism in Drug Discovery

Mitigating Heterocycle Metabolism in Drug Discovery

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

Identification of 1-Methyl-<i>N</i>-(propan-2-yl)-<i>N</i>-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1<i>H</i>-imidazole-4-carboxamide as a Potent and Orally Available Glycine Transporter 1 Inhibitor

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