Publications by authors named "Frederic Zécri"

18 Publications

  • Page 1 of 1

Water-Compatible Cycloadditions of Oligonucleotide-Conjugated Strained Allenes for DNA-Encoded Library Synthesis.

J Am Chem Soc 2020 04 16;142(17):7776-7782. Epub 2020 Apr 16.

Chemical Biology and Therapeutics Science Program, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.

DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-discovery efforts. Combinatorial syntheses of such libraries require water- and DNA-compatible reactions, and the paucity of these reactions currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with activated olefins, 1,3-dipoles, and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-barcoded compounds exhibit unprecedented ring and topographic features, related to elements found to be powerful in phenotypic screening.
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http://dx.doi.org/10.1021/jacs.9b13186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294439PMC
April 2020

A Phenotypic Screen Identifies Calcium Overload as a Key Mechanism of β-Cell Glucolipotoxicity.

Diabetes 2020 05 20;69(5):1032-1041. Epub 2020 Feb 20.

Novartis Institutes for BioMedical Research, Cambridge, MA

Type 2 diabetes (T2D) is caused by loss of pancreatic β-cell mass and failure of the remaining β-cells to deliver sufficient insulin to meet demand. β-Cell glucolipotoxicity (GLT), which refers to combined, deleterious effects of elevated glucose and fatty acid levels on β-cell function and survival, contributes to T2D-associated β-cell failure. Drugs and mechanisms that protect β-cells from GLT stress could potentially improve metabolic control in patients with T2D. In a phenotypic screen seeking low-molecular-weight compounds that protected β-cells from GLT, we identified compound A that selectively blocked GLT-induced apoptosis in rat insulinoma cells. Compound A and its optimized analogs also improved viability and function in primary rat and human islets under GLT. We discovered that compound A analogs decreased GLT-induced cytosolic calcium influx in islet cells, and all measured β-cell-protective effects correlated with this activity. Further studies revealed that the active compound from this series largely reversed GLT-induced global transcriptional changes. Our results suggest that taming cytosolic calcium overload in pancreatic islets can improve β-cell survival and function under GLT stress and thus could be an effective strategy for T2D treatment.
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http://dx.doi.org/10.2337/db19-0813DOI Listing
May 2020

Successful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor.

ACS Med Chem Lett 2019 Aug 20;10(8):1128-1133. Epub 2019 Jun 20.

Global Discovery Chemistry, Cardiovascular and Metabolism, and PK Sciences, Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Diacylglycerol -acyltransferase 1 (DGAT1) inhibitor Pradigastat () was shown to be effective at decreasing postprandial triglyceride levels in a patient population with familial chylomicronemia syndrome (FCS). Although pradigastat does not cause photosensitization in humans at the high clinical dose of 40 mg, a positive signal was observed in preclinical models of phototoxicity. Herein, we describe a preclinical phototoxicity mitigation strategy for diarylamine containing molecules utilizing the introduction of an amide or suitable heterocyclic function. This strategy led to the development of two second-generation compounds with low risk of phototoxicity, disparate exposure profiles, and comparable efficacy to in a rodent lipid bolus model for post-prandial plasma triglycerides.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691483PMC
August 2019

3'-Modification stabilizes mRNA and increases translation in cells.

Bioorg Med Chem Lett 2018 08 4;28(14):2451-2453. Epub 2018 Jun 4.

Novartis Institutes for BioMedical Research, 181 Massachusetts Ave., Cambridge, MA 02139, USA.

Successful implementation of mRNA gene therapy is facing many hurdles, for example poor expression levels of the exogenously delivered mRNA transcripts. Herein we describe the synthesis of various 3'-modified RNA oligonucleotides, and we show that 3'-modification drastically stabilizes these oligonucleotides in cell extracts. Modification of the 3'-terminus of gaussia luciferase mRNA results in 3-fold increased and extended (>48 h) translation of the mRNA. Our findings suggest 3'-modification of RNA-transcripts as a valid approach to increase expression levels for application in mRNA gene therapy.
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http://dx.doi.org/10.1016/j.bmcl.2018.06.008DOI Listing
August 2018

Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors.

ACS Med Chem Lett 2017 Sep 25;8(9):975-980. Epub 2017 Aug 25.

Global Discovery Chemistry, PK Sciences, Chemical Biology and Therapeutics, and Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.

The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and β isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kδ selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. , CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. , CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kδ and PI3Kγδ-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjögren's syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kδ.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601375PMC
September 2017

Predictive Model for Site-Selective Aryl and Heteroaryl C-H Functionalization via Organic Photoredox Catalysis.

J Am Chem Soc 2017 08 7;139(32):11288-11299. Epub 2017 Aug 7.

Department of Chemistry, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599-3290, United States.

Direct C-H functionalization of aromatic compounds is a useful synthetic strategy that has garnered much attention because of its application to pharmaceuticals, agrochemicals, and late-stage functionalization reactions on complex molecules. On the basis of previous methods disclosed by our lab, we sought to develop a predictive model for site selectivity and extend this aryl functionalization chemistry to a selected set of heteroaromatic systems commonly used in the pharmaceutical industry. Using electron density calculations, we were able to predict the site selectivity of direct C-H functionalization in a number of heterocycles and identify general trends observed across heterocycle classes.
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http://dx.doi.org/10.1021/jacs.7b06715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996966PMC
August 2017

Medicinal Chemistry Profiling of Monocyclic 1,2-Azaborines.

ChemMedChem 2017 03 21;12(5):358-361. Epub 2017 Feb 21.

Department of Chemistry, Boston College, Chestnut Hill, MA, 02467, USA.

The first examples of biologically active monocyclic 1,2-azaborines have been synthesized and demonstrated to exhibit not only improved in vitro aqueous solubility in comparison with their corresponding carbonaceous analogues, but in the context of a CDK2 inhibitor, also improved biological activity and better in vivo oral bioavailability. This proof-of-concept study establishes the viability of monocyclic 1,2-azaborines as a novel pharmacophore with distinct pharmacological profiles that can help address challenges associated with solubility in drug development research.
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http://dx.doi.org/10.1002/cmdc.201700047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654323PMC
March 2017

Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties.

Bioorg Med Chem Lett 2016 12 27;26(23):5657-5662. Epub 2016 Oct 27.

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.

In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.
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http://dx.doi.org/10.1016/j.bmcl.2016.10.069DOI Listing
December 2016

Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

ACS Med Chem Lett 2016 Aug 2;7(8):762-7. Epub 2016 Jun 2.

Global Discovery Chemistry, Center for Proteomic Chemistry, Metabolism and Pharmacokinetics, Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research , Novartis Campus, CH-4002 Basel, Switzerland.

Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983741PMC
August 2016

Covalent Chemical 5'-Functionalization of RNA with Diazo Reagents.

Angew Chem Int Ed Engl 2016 08 19;55(35):10283-6. Epub 2016 Jul 19.

Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA.

Functionalization of RNA at the 5'-terminus is important for analytical and therapeutic purposes. Currently, these RNAs are synthesized de novo starting with a chemically functionalized 5'-nucleotide, which is incorporated into RNA using chemical synthesis or biochemical techniques. Methods for direct chemical modification of native RNA would provide an attractive alternative but are currently underexplored. Herein, we report that diazo compounds can be used to selectively alkylate the 5'-phosphate of ribo(oligo)nucleotides to give RNA labelled through a native phosphate ester bond. We applied this method to functionalize oligonucleotides with biotin and an orthosteric inhibitor of the eukaryotic initiation factor 4E (eIF4E), an enzyme involved in mRNA recognition. The modified RNA binds to eIF4E, demonstrating the utility of this labelling technique to modulate biological activity of RNA. This method complements existing techniques and may be used to chemically introduce a broad range of functional handles at the 5'-end of RNA.
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http://dx.doi.org/10.1002/anie.201604385DOI Listing
August 2016

From Natural Product to the First Oral Treatment for Multiple Sclerosis: The Discovery of FTY720 (Gilenya™)?

Curr Opin Chem Biol 2016 06 31;32:60-6. Epub 2016 May 31.

Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. Electronic address:

Multiple sclerosis is a devastating chronic autoimmune disease affecting women and men of all ages. Inflammation of the central nervous system causes demyelination and ultimately neuropsychological dysfunction. Myriocin, a natural product with strong immunosuppressant activity was interrogated leading to a new class of immunomodulator with a unique mode of action. In this review, we will summarize these findings, the mechanism hypothesis and discuss the data's ultimately leading to the approval of Gilenya™ as the first oral treatment for multiple sclerosis.
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http://dx.doi.org/10.1016/j.cbpa.2016.04.014DOI Listing
June 2016

The design and implementation of a generic lipopeptide scanning platform to enable the identification of 'locally acting' agonists for the apelin receptor.

Bioorg Med Chem Lett 2014 Oct 28;24(20):4871-5. Epub 2014 Aug 28.

Novartis Institutes for BioMedical Research, Technology Square, Cambridge, MA 02139, USA.

This Letter describes methodology to enable the identification of tool or therapeutic lipopeptides which modulate the function of membrane bound proteins. The choice of lipopeptides as a chemotype is the amalgamation of multiple medicinal chemistry considerations including duration of action, low systemic exposure and access to intracellular components. The 'lipopeptide shuffle' has been applied here to the APJ receptor and has rapidly resulted in the discovery of a 33 nM APJ agonist hit from an initial 369 member lipopeptide synthetic array.
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http://dx.doi.org/10.1016/j.bmcl.2014.08.045DOI Listing
October 2014

Absorption and disposition of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in healthy volunteers: a case of xenobiotic biotransformation following endogenous metabolic pathways.

Drug Metab Dispos 2011 Feb 2;39(2):199-207. Epub 2010 Nov 2.

Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland.

Fingolimod [(FTY720), Gilenya; 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol], a new drug for the treatment of relapsing multiple sclerosis, acts through its phosphate metabolite, which modulates sphingosine 1-phosphate receptors. This represents a novel mechanism of action. In the present work, the absorption and disposition of (14)C-labeled fingolimod were investigated in healthy male volunteers after a single oral dose of 4.5 mg. Total radioactivity was determined in blood, urine, and feces. Fingolimod was quantified in blood. Metabolite profiles were determined in blood and excreta, and metabolite structures were elucidated by mass spectrometry, wet-chemical methods, and comparison with reference compounds. Fingolimod was absorbed slowly but almost completely. The biotransformation of fingolimod involved three main pathways: 1) reversible phosphorylation to fingolimod phosphate [(S)-enantiomer, active principle]; 2) ω-hydroxylation at the octyl chain, catalyzed predominantly by CYP4F enzymes, followed by further oxidation to a carboxylic acid and subsequent β-oxidation; and 3) formation of ceramide analogs by conjugation with endogenous fatty acids. This metabolism is quite unusual because it follows metabolic pathways of structurally related endogenous compounds rather than biotransformations typical for xenobiotics. The elimination of fingolimod was slow and occurred predominantly by oxidative metabolism whereas fingolimod phosphate was eliminated mainly by dephosphorylation back to fingolimod. Drug-related material was excreted mostly in the urine in the form of oxidation products.
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http://dx.doi.org/10.1124/dmd.110.035907DOI Listing
February 2011

Pyrazole derived from (+)-3-carene; a novel potent, selective scaffold for sphingosine-1-phosphate (S1P(1)) receptor agonists.

Bioorg Med Chem Lett 2010 Jan 15;20(1):35-7. Epub 2009 Nov 15.

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

High throughput screening and hit to lead optimization led to the identification of 'carene' as a promising scaffold showing selective S1P(1) receptor agonism. In parallel to this work we have established a pharmacophore model for the S1P(1) receptor highlighting the minimal structural requirement necessary for potent receptor agonism.
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http://dx.doi.org/10.1016/j.bmcl.2009.11.045DOI Listing
January 2010

Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors.

Nat Chem Biol 2009 Jun;5(6):428-34

Developmental & Molecular Pathways and 2Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.

Targeting sphingosine-1-phosphate receptors with the oral immunomodulator drug FTY720 (fingolimod) has demonstrated substantial efficacy in the treatment of multiple sclerosis. The drug is phosphorylated in vivo, and most of the clinical effects of FTY720-phosphate (FTY720P) are thought to be mediated via S1P1 receptors on lymphocytes and endothelial cells, leading to sequestration of lymphocytes in secondary lymphoid organs. FTY720P was described to act as a "functional antagonist" by promoting efficient internalization of S1P1 receptors. We demonstrate here that S1P1 receptors activated by FTY720P retain signaling activity for hours in spite of a quantitative internalization. Structural analogs of FTY720P with shorter alkyl side chains retained potency and efficacy in a functional assay but failed to promote long-lasting receptor internalization and signaling. We show that persistent signaling translates into an increased chemokinetic migration of primary human umbilical vein endothelial cells, which suggests persistent agonism as a crucial parameter in the mechanism of action of FTY720.
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http://dx.doi.org/10.1038/nchembio.173DOI Listing
June 2009

Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer.

J Med Chem 2005 Aug;48(16):5373-7

Novartis Institutes for BioMedical Research, Lichtstrasse 35, WSJ-507.3.02, CH-4056 Basel, Switzerland.

In vivo phosphorylation of FTY720 (1) in rats and humans resulted exclusively in the biologically active (S)-configured enantiomer, which was proven by an ex vivo o-phthaldialdehyde derivatization protocol especially elaborated for phosphates of 1. Starting from the prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after purification of a partially protected key intermediate on an enantioselective support. The absolute stereochemistry was determined by X-ray diffraction.
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http://dx.doi.org/10.1021/jm050242fDOI Listing
August 2005

Total synthesis of thiostrepton. Retrosynthetic analysis and construction of key building blocks.

J Am Chem Soc 2005 Aug;127(31):11159-75

Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

The first phase of the total synthesis of thiostrepton (1), a highly complex thiopeptide antibiotic, is described. After a brief introduction to the target molecule and its structural motifs, it is shown that retrosynthetic analysis of thiostrepton reveals compounds 23, 24, 26, 28, and 29 as potential key building blocks for the projected total synthesis. Concise and stereoselective constructions of all these intermediates are then described. The synthesis of the dehydropiperidine core 28 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 24 and the thiazoline-thiazole segment 26 were synthesized by a series of reactions that included asymmetric and other stereoselective processes. The dehydroalanine tail precursor 23 and the alanine equivalent 29 were also prepared from the appropriate amino acids. Finally, a method was developed for the direct coupling of the labile dehydropiperidine key building block 28 to the more advanced and stable peptide intermediate 27 through capture with the highly reactive alanine equivalent 67 under conditions that avoided the initially encountered destructive ring contraction process.
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http://dx.doi.org/10.1021/ja0529337DOI Listing
August 2005

Stereocontrolled synthesis of the quinaldic acid macrocyclic system of thiostrepton.

Angew Chem Int Ed Engl 2002 Jun;41(11):1937-40

Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

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June 2002