N-Benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors

Atkinson, Karen; Beretta, Elena; Brown, Janice A.; Castrodad, Mayda; Chen, Yue; Cosgrove, Judith M.; Du, Ping; Litchfield, John; Makowski, M.; Martin, Kelly A.; McLellan, Thomas J.; Neagu, Constantin; Perry, David A.; Piotrowski, David W.; Steppan, Claire M.; Trilles, Richard

doi:10.1016/j.bmcl.2011.01.113

Cited by 36 publications

(19 citation statements)

References 18 publications

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“…5b Is an Orally Available SCD Inhibitor Active in Brain An iterative library design had previously identified 5b as an appropriate tool compound to inhibit SCD for potential use in models of obesity. 31 In rats, 5b achieved high exposure in vivo to effect dose-dependent decreases of the plasma and liver DI (MUFA to saturated FA [SFA]; eg, 16:1 to 16:0 and 18:1 to 18:0). 31 To further evaluate the pharmacokinetic (PK) properties of 5b, we assessed the bioavailability of the drug in 3-month-old Ntg C57Bl6 mice after single doses of 3 mg/kg intravenous or 10 mg/ kg per os (PO), using standard pharmacokinetic (PK) parameters (Fig 1).…”

Section: Resultsmentioning

confidence: 99%

“…31 In rats, 5b achieved high exposure in vivo to effect dose-dependent decreases of the plasma and liver DI (MUFA to saturated FA [SFA]; eg, 16:1 to 16:0 and 18:1 to 18:0). 31 To further evaluate the pharmacokinetic (PK) properties of 5b, we assessed the bioavailability of the drug in 3-month-old Ntg C57Bl6 mice after single doses of 3 mg/kg intravenous or 10 mg/ kg per os (PO), using standard pharmacokinetic (PK) parameters (Fig 1). A C max of 4,413ng/ml in plasma was achieved after 60 minutes of PO dosing.…”

Section: Resultsmentioning

confidence: 99%

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A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α‐Synuclein Mice

Nuber

Nam

Rajsombath

et al. 2020

Annals of Neurology

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Objective Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease‐modifying treatments are approved. A key therapeutic target in PD is α‐synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl–coenzyme A desaturase (SCD) inhibitor (“5b”) that prevented αS‐positive vesicular inclusions and cytotoxicity in cultured human neurons. Methods Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild‐type human αS (WT) or an amplified familial PD αS mutation (E35K + E46K + E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD‐like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD‐related lipid changes were quantified in 5b‐ versus placebo‐treated mice. Outcomes were compared to effects of crossing 3K to SCD1−/− mice. Results 5b treatment reduced αS hyperphosphorylation in E46K‐expressing human neurons, in 3K neural cultures, and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD‐like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS tetramers and reduced proteinase K‐resistant lipid‐rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation. Interpretation Prolonged reduction of brain SCD activity prevented PD‐like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human α‐synucleinopathies. ANN NEUROL 2021;89:74–90

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α‐Synuclein Mice

Nuber

Nam

Rajsombath

et al. 2020

Annals of Neurology

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“…The speed and efficiency of the HT-MS/MS can allow for experiments that would otherwise be deemed “untenable” under normal circumstances. The HT system has been validated as suitable for many drug discoveries [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ] and ADME (Absorption, Distribution, Metabolism and Excretion) based applications [ 66 ]. The main drawback of this method is that disaccharides with identical molecular weights cannot be distinguished.…”

Section: History Of Gag Assay By Tandem Mass Spectrometry (Ms/ms)mentioning

confidence: 99%

Establishment of Glycosaminoglycan Assays for Mucopolysaccharidoses

et al. 2014

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Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of the lysosomal enzymes essential for catabolism of glycosaminoglycans (GAGs). Accumulation of undegraded GAGs results in dysfunction of multiple organs, resulting in distinct clinical manifestations. A range of methods have been developed to measure specific GAGs in various human samples to investigate diagnosis, prognosis, pathogenesis, GAG interaction with other molecules, and monitoring therapeutic efficacy. We established ELISA, liquid chromatography tandem mass spectrometry (LC-MS/MS), and an automated high-throughput mass spectrometry (HT-MS/MS) system (RapidFire) to identify epitopes (ELISA) or disaccharides (MS/MS) derived from different GAGs (dermatan sulfate, heparan sulfate, keratan sulfate, and/or chondroitin sulfate). These methods have a high sensitivity and specificity in GAG analysis, applicable to the analysis of blood, urine, tissues, and cells. ELISA is feasible, sensitive, and reproducible with the standard equipment. HT-MS/MS yields higher throughput than conventional LC-MS/MS-based methods while the HT-MS/MS system does not have a chromatographic step and cannot distinguish GAGs with identical molecular weights, leading to a limitation of measurements for some specific GAGs. Here we review the advantages and disadvantages of these methods for measuring GAG levels in biological specimens. We also describe an unexpected secondary elevation of keratan sulfate in patients with MPS that is an indirect consequence of disruption of catabolism of other GAGs.

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“…By replacing the high-performance liquid chromatography (HPLC) unit of the traditional liquid chromatography/mass spectrometry (LC/MS) system with a low-volume sample clean-up cartridge, it is able to operate at high flow rates, enabling the processing of quenched samples directly from a 384-well plate at a rate of approximately 6 to 8 s per well, enabling analysis of a 384-well plate to be completed in 45 min. Encouraged by several recent successful screens using RF-MS technology, [19][20][21][22][23][24] we investigated the feasibility of using the platform for assay of the HKDMs. Here, we describe the development of an RF-MS assay for HKDMs that demethylate H3K9 and its successful implementation to screen 101 226 compounds against JMJD2C.…”

Section: Introductionmentioning

confidence: 99%

Enabling Lead Discovery for Histone Lysine Demethylases by High-Throughput RapidFire Mass Spectrometry

Hutchinson

Leveridge²,

Heathcote³

et al. 2012

SLAS Discovery

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A high-throughput RapidFire mass spectrometry assay is described for the JMJD2 family of Fe(2+), O(2), and α-ketoglutarate-dependent histone lysine demethylases. The assay employs a short amino acid peptide substrate, corresponding to the first 15 amino acid residues of histone H3, but mutated at two positions to increase assay sensitivity. The assay monitors the direct formation of the dimethylated-Lys9 product from the trimethylated-Lys9 peptide substrate. Monitoring the formation of the monomethylated and des-methylated peptide products is also possible. The assay was validated using known inhibitors of the histone lysine demethylases, including 2,4-pyridinedicarboxylic acid and an α-ketoglutarate analogue. With a sampling rate of 7 s per well, the RapidFire technology permitted the single-concentration screening of 101 226 compounds against JMJD2C in 10 days using two instruments, typically giving Z' values of 0.75 to 0.85. Several compounds were identified of the 8-hydroxyquinoline chemotype, a known series of inhibitors of the Lys9-specific histone demethylases. The peptide also functions as a substrate for JMJD2A, JMJD2D, and JMJD2E, thus enabling the development of assays for all 3 enzymes to monitor progress in compound selectivity. The assay represents the first report of a RapidFire mass spectrometry assay for an epigenetics target.

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N-Benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors

Cited by 36 publications

References 18 publications

A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α‐Synuclein Mice

A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α‐Synuclein Mice

Establishment of Glycosaminoglycan Assays for Mucopolysaccharidoses

Enabling Lead Discovery for Histone Lysine Demethylases by High-Throughput RapidFire Mass Spectrometry

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