Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase

Butler, Christopher R.; Beck, Elizabeth M.; Harris, Anthony R.; Huang, Zhen; McAllister, Laura A.; Ende, Christopher W. am; Fennell, Kimberly F.; Foley, Timothy L.; Fonseca, Kari R.; Hawrylik, Steven J.; Johnson, Douglas S.; Knafels, John D.; Mente, Scot; Noell, Stephen; Pandit, Jayvardhan; Phillips, Tracy B.; Piro, Justin R.; Rogers, Bruce N.; Samad, Tarek A.; Wang, Jane; Wan, Shuangyi; Brodney, Michael A.

doi:10.1021/acs.jmedchem.7b01531

Cited by 60 publications

(75 citation statements)

References 33 publications

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“…The fact that plasma FFAs are linked to insulin resistance (Schweiger et al, 2017) and neuroinflammation (Butler et al, 2017) renders lipolysis an attractive target to improve insulin sensitivity. HSL and MGL are crucial lipases involved in lipolysis and degradation of stored triglycerides into FFA and glycerol (Bolsoni-Lopes & Alonso-Vale, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Elevated levels of circulating FFA play crucial role in insulin resistance and, hence, in the pathogenesis of type II diabetes mellitus (Arner, 2003;Karpe, Dickmann, & Frayn, 2011;Morigny, Houssier, Mouisel, & Langin, 2016;Schweiger et al, 2017). Moreover, MGL is involved in neuroinflammation by releasing proinflammatory eicosanoids and cytokines (Butler et al, 2017;Fowler, 2012;Grabner, Zimmermann, Schicho, & Taschler, 2017). The pivotal role of HSL and MGL in lipolysis makes them promising targets to develop new lipase inhibitors for the treatment of neuroinflammatory disorders and insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

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The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation

2019

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Lipolysis is primarily controlled by the stepwise action of hormone‐sensitive lipase (HSL) and monoglyceride lipase (MGL) to release free fatty acids and glycerol. A high level of circulating free fatty acids is well‐known to mediate insulin resistance. Thus, the need to discover lipase inhibitors against both enzyme systems remains urgent. Agrochemicals are tightly regulated chemicals and therefore are potential source of new medicinal agents. Accordingly, we implemented a computational workflow to search for new lipase inhibitory leads by virtually screening commercial agrochemicals against HSL and MGL employing binding pharmacophores and docking experiments. Ten agrochemicals were identified as potential lipase inhibitors, out of which quinclorac, a safe herbicide, achieved high‐ranking score. Subsequent in vitro evaluation against rat epididymal lipase activity showed quinclorac to exhibit nanomolar anti‐lipase IC50. Subsequent in vivo testing showed quinclorac to significantly decrease blood glycerol levels after acute exposure (150 mg/kg) and multiple dosing (50 or 25 mg/kg) (p < 0.05).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation

2019

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“…An efficient drug design requires potency to be achieved with a minimal increase in MW or lipophilicity [21][22][23][24].…”

Section: Lipophilicitymentioning

confidence: 99%

Leveraging chromatography based physicochemical properties for efficient drug design

Goetz

Shalaeva²

2018

ADMET DMPK

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<p class="ADMETabstracttext">Applications of chromatography derived lipophilicity, polarity, and 3D concepts such as conformational states, exposed polarity and intramolecular hydrogen bonds (IMHB), are discussed along with recently developed methods for incorporating these concepts into drug design strategies. In addition, the drug design process is described with examples and practices used at Pfizer, as well as experimental and computed parameters used for parallel optimization of properties leading to drug candidate nominations.</p>

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“…ABD-1970 ( Fig. 1) is a member of the carbamate class of MGLL inhibitors, which have been shown to act via covalent carbamylation of the active-site serine residue (Long et al, 2009a;Chang et al, 2012;Niphakis et al, 2012;Griebel et al, 2015;Butler et al, 2017). Characterization of ABD-1970 potency and selectivity leveraged ABPP, a chemical proteomics platform that utilizes active site-directed chemical probes to evaluate the activity of entire enzyme families in parallel in native biologic matrices (Simon and Cravatt, 2010).…”

Section: Abd-1970 Is a Potent And Selective Inhibitor Of Mgll Across mentioning

confidence: 99%

Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators

Clapper¹,

Henry²,

Niphakis³

et al. 2018

J Pharmacol Exp Ther

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Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurologic disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 [1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)piperazine-1carboxylate]. We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations, and efficacy. Because MGLL contributes to arachidonic acid metabolism in a subset of rodent tissues, we further used ABD-1970 to evaluate whether selective MGLL inhibition would affect prostanoid production in several human assays known to be sensitive to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and antipruritic activity in a battery of rodent models (ED 50 values of 1-2 mg/kg). The antinociceptive effects of ABD-1970 were potentiated when combined with analgesic standards of care and occurred without overt cannabimimetic effects. ABD-1970 also blocked 2-AG hydrolysis in human brain tissue and elevated 2-AG content in human blood without affecting stimulated prostanoid production. These findings support the clinical development of MGLL inhibitors as a differentiated mechanism to treat pain and other neurologic disorders.

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Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase

Cited by 60 publications

References 33 publications

The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation

The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation

Leveraging chromatography based physicochemical properties for efficient drug design

Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators

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