Publications by authors named "Stephen Noell"

14 Publications

  • Page 1 of 1

Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19.

J Med Chem 2020 11 15;63(21):12725-12747. Epub 2020 Oct 15.

Southern Research Institute, 2000 9th Avenue South, Birmingham, Alabama 35205 United States.

The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CL) in a post-translational processing step that is critical for coronavirus replication. The 3CL sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CL employing ligand-protease structures solved by X-ray crystallography led to the identification of and . Preclinical experiments reveal () as a potent inhibitor of CoV-2 3CL with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571312PMC
November 2020

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19.

bioRxiv 2020 Sep 13. Epub 2020 Sep 13.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential to the viral life cycle across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835231 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, and in vitro antiviral activity data to warrant clinical evaluation.
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http://dx.doi.org/10.1101/2020.09.12.293498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491518PMC
September 2020

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

Draft Genome Sequence of sp. Strain PC23-8, Isolated from a Freshwater Stream Impacted by Acid Mine Drainage.

Microbiol Resour Announc 2019 Oct 10;8(41). Epub 2019 Oct 10.

Department of Biology, Geneva College, Beaver Falls, Pennsylvania, USA

We present the draft genome sequence of sp. strain PC23-8, a bacterium isolated from freshwater stream sediment downstream from acid mine drainage. The 6.4-Mb genome sequence of this strain contains several secondary metabolite gene clusters, including one similar to the cyclic peptide jagaricin, synthesized by .
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http://dx.doi.org/10.1128/MRA.00850-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787320PMC
October 2019

SAR11 bacteria have a high affinity and multifunctional glycine betaine transporter.

Environ Microbiol 2019 07 21;21(7):2559-2575. Epub 2019 May 21.

Department of Microbiology, Oregon State University, Corvallis, OR, USA.

Marine bacterioplankton face stiff competition for limited nutrient resources. SAR11, a ubiquitous clade of very small and highly abundant Alphaproteobacteria, are known to devote much of their energy to synthesizing ATP-binding cassette periplasmic proteins that bind substrates. We hypothesized that their small size and relatively large periplasmic space might enable them to outcompete other bacterioplankton for nutrients. Using uptake experiments with C-glycine betaine, we discovered that two strains of SAR11, Candidatus Pelagibacter sp. HTCC7211 and Cand. P. ubique HTCC1062, have extraordinarily high affinity for glycine betaine (GBT), with half-saturation (K ) values around 1 nM and specific affinity values between 8 and 14 L mg cell  h . Competitive inhibition studies indicated that the GBT transporters in these strains are multifunctional, transporting multiple substrates in addition to GBT. Both strains could use most of the transported compounds for metabolism and ATP production. Our findings indicate that Pelagibacter cells are primarily responsible for the high affinity and multifunctional GBT uptake systems observed in seawater. Maximization of whole-cell affinities may enable these organisms to compete effectively for nutrients during periods when the gross transport capacity of the heterotrophic plankton community exceeds the supply, depressing ambient concentrations.
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http://dx.doi.org/10.1111/1462-2920.14649DOI Listing
July 2019

A Parasitic Arsenic Cycle That Shuttles Energy from Phytoplankton to Heterotrophic Bacterioplankton.

mBio 2019 03 19;10(2). Epub 2019 Mar 19.

Department of Microbiology, Oregon State University, Corvallis, Oregon, USA.

In many regions of the world oceans, phytoplankton face the problem of discriminating between phosphate, an essential nutrient, and arsenate, a toxic analogue. Many phytoplankton, including the most abundant phytoplankton group known, , detoxify arsenate (AsV) by reduction to arsenite (AsIII), followed by methylation and excretion of the methylated arsenic products. We synthesized [C]dimethyl arsenate (DMA) and used it to show that cultured strain HTCC7211 (SAR11) cells oxidize the methyl group carbons of DMA, producing CO and ATP. We measured [C]DMA oxidation rates in the P-depleted surface waters of the Sargasso Sea, a subtropical ocean gyre. [C]DMA was oxidized to CO by Sargasso Sea plankton communities at a rate that would cause turnover of the estimated DMA standing stock every 8.1 days. SAR11 strain HTCC7211, which was isolated from the Sargasso Sea, has a pair of arsenate resistance genes and was resistant to arsenate, showing no growth inhibition at As/P ratios of >65:1. Across the global oceans, there was a strong inverse relationship between the frequency of the arsenate reductase (LMWPc_ArsC) in genomes and phosphate concentrations. We propose that the demethylation of methylated arsenic compounds by and possibly other bacterioplankton, coupled with arsenate resistance, results in the transfer of energy from phytoplankton to bacteria. We dub this a parasitic cycle because the release of arsenate by in principle creates a positive-feedback loop that forces phytoplankton to continually regenerate arsenate detoxification products, producing a flow of energy to P-limited ocean regions. In vast, warm regions of the oceans, phytoplankton face the problem of arsenic poisoning. Arsenate is toxic because it is chemically similar to phosphate, a scarce nutrient that phytoplankton cells need for growth. Many phytoplankton, including the commonest phytoplankton type in warm oceans, , detoxify arsenate by adding methyl groups. Here we show that the most abundant non-photosynthetic plankton in the oceans, SAR11 bacteria, remove the methyl groups, releasing poisonous forms of arsenic back into the water. We postulate that the methylation and demethylation of arsenic compounds creates a cycle in which the phytoplankton can never get ahead and must continually transfer energy to the SAR11 bacteria. We dub this a parasitic process and suggest that it might help explain why SAR11 bacteria are so successful, surpassing all other plankton in their numbers. Field experiments were done in the Sargasso Sea, a subtropical ocean gyre that is sometimes called an ocean desert because, throughout much of the year, there is not enough phosphorous in the water to support large blooms of phytoplankton. Ocean deserts are expanding as the oceans absorb heat and grow warmer.
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http://dx.doi.org/10.1128/mBio.00246-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426599PMC
March 2019

Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation.

J Med Chem 2018 04 15;61(7):3008-3026. Epub 2018 Mar 15.

Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States.

Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log  D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00070DOI Listing
April 2018

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

J Med Chem 2017 12 5;60(23):9860-9873. Epub 2017 Dec 5.

Pfizer Worldwide Research and Development , 1 Portland Street, Cambridge, Massachusetts 02139, United States.

Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01531DOI Listing
December 2017

Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA).

J Med Chem 2017 04 16;60(7):3094-3108. Epub 2017 Mar 16.

Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.

The C-5 substituted 2,4-diaminoquinazoline RG3039 (compound 1), a member of a chemical series that was identified and optimized using an SMN2 promoter screen, prolongs survival and improves motor function in a mouse model of spinal muscular atrophy (SMA). It is a potent inhibitor of the mRNA decapping scavenger enzyme (DcpS), but the mechanism whereby DcpS inhibition leads to therapeutic benefit is unclear. Compound 1 is a dibasic lipophilic molecule that is predicted to accumulate in lysosomes. To understand if the in vivo efficacy is due to DcpS inhibition or other effects resulting from the physicochemical properties of the chemotype, we undertook structure based molecular design to identify DcpS inhibitors with improved physicochemical properties. Herein we describe the design, synthesis, and in vitro pharmacological characterization of these DcpS inhibitors along with the in vivo mouse CNS PK profile of PF-DcpSi (compound 24), one of the analogs found to be efficacious in SMA mouse model.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00124DOI Listing
April 2017

Tool compounds robustly increase turnover of an artificial substrate by glucocerebrosidase in human brain lysates.

PLoS One 2015 12;10(3):e0119141. Epub 2015 Mar 12.

Pfizer Neuroscience Research Unit, 610 Main Street, Cambridge, MA, United States of America.

Mutations in glucocerebrosidase (GBA1) cause Gaucher disease and also represent a common risk factor for Parkinson's disease and Dementia with Lewy bodies. Recently, new tool molecules were described which can increase turnover of an artificial substrate 4MUG when incubated with mutant N370S GBA1 from human spleen. Here we show that these compounds exert a similar effect on the wild-type enzyme in a cell-free system. In addition, these tool compounds robustly increase turnover of 4MUG by GBA1 derived from human cortex, despite substantially lower glycosylation of GBA1 in human brain, suggesting that the degree of glycosylation is not important for compound binding. Surprisingly, these tool compounds failed to robustly alter GBA1 turnover of 4MUG in the mouse brain homogenate. Our data raise the possibility that in vivo models with humanized glucocerebrosidase may be needed for efficacy assessments of such small molecules.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119141PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357465PMC
November 2015

Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor.

J Med Chem 2015 Jan 17;58(1):419-32. Epub 2014 Nov 17.

Worldwide Medicinal Chemistry, ‡Neuroscience Research Unit, and §Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.
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http://dx.doi.org/10.1021/jm5014055DOI Listing
January 2015

Kinase domain inhibition of leucine rich repeat kinase 2 (LRRK2) using a [1,2,4]triazolo[4,3-b]pyridazine scaffold.

Bioorg Med Chem Lett 2014 Sep 30;24(17):4132-40. Epub 2014 Jul 30.

Neuroscience Research Unit, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand-protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.
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http://dx.doi.org/10.1016/j.bmcl.2014.07.052DOI Listing
September 2014

Phosphoproteomic evaluation of pharmacological inhibition of leucine-rich repeat kinase 2 reveals significant off-target effects of LRRK-2-IN-1.

J Neurochem 2014 Feb 11;128(4):561-76. Epub 2013 Nov 11.

Pfizer Global Research & Development, Neuroscience Research Unit, Cambridge, MA, USA.

Genetic mutations in leucine-rich repeat kinase 2 (LRRK2) have been linked to autosomal dominant Parkinson's disease. The most prevalent mutation, G2019S, results in enhanced LRRK2 kinase activity that potentially contributes to the etiology of Parkinson's disease. Consequently, disease progression is potentially mediated by poorly characterized phosphorylation-dependent LRRK2 substrate pathways. To address this gap in knowledge, we transduced SH-SY5Y neuroblastoma cells with LRRK2 G2019S via adenovirus, then determined quantitative changes in the phosphoproteome upon LRRK2 kinase inhibition (LRRK2-IN-1 treatment) using stable isotope labeling of amino acids in culture combined with phosphopeptide enrichment and LC-MS/MS analysis. We identified 776 phosphorylation sites that were increased or decreased at least 50% in response to LRRK2-IN-1 treatment, including sites on proteins previously known to associate with LRRK2. Bioinformatic analysis of those phosphoproteins suggested a potential role for LRRK2 kinase activity in regulating pro-inflammatory responses and neurite morphology, among other pathways. In follow-up experiments, LRRK2-IN-1 inhibited lipopolysaccharide-induced tumor necrosis factor alpha (TNFα) and C-X-C motif chemokine 10 (CXCL10) levels in astrocytes and also enhanced multiple neurite characteristics in primary neuronal cultures. However, LRRK2-IN-1 had almost identical effects in primary glial and neuronal cultures from LRRK2 knockout mice. These data suggest LRRK2-IN-1 may inhibit pathways of perceived LRRK2 pathophysiological function independently of LRRK2 highlighting the need to use multiple pharmacological tools and genetic approaches in studies determining LRRK2 function.
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http://dx.doi.org/10.1111/jnc.12483DOI Listing
February 2014

Discovery and optimization of a novel spiropyrrolidine inhibitor of β-secretase (BACE1) through fragment-based drug design.

J Med Chem 2012 Nov 9;55(21):9069-88. Epub 2012 May 9.

Pfizer Worldwide Research, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United States.

The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.
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http://dx.doi.org/10.1021/jm201715dDOI Listing
November 2012