799
Views
5
CrossRef citations to date
0
Altmetric
Review

O-GlcNAcase inhibitors as potential therapeutics for the treatment of Alzheimer’s disease and related tauopathies: analysis of the patent literature

, , &
Pages 1117-1154 | Received 05 Mar 2021, Accepted 21 Jun 2021, Published online: 08 Jul 2021

References

  • Torres CR, Hart GW. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact. Evidence for O-linked GlcNAclymphocytes. J Biol Chem. 1984;259(5):3308–3317.
  • Holt GD, Hart GW. The subcellular distribution of terminal N-acetylglucosamine moieties. Localization of a novel protein-saccharide linkage, O-linked GlcNAc. J Biol Chem. 1986;261(17):8049–8057.
  • Wells L, Vosseller K, Hart GW. Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. Science. 2001;291(5512):2376–2378.
  • Gao Y, Wells L, Comer FI, et al. Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain. J Biol Chem. 2001;276(13):9838–9845.
  • Wells L, Gao Y, Mahoney JA, et al. Dynamic O-glycosylation of nuclear and cytosolic proteins: further characterization of the nucleocytoplasmic beta-N-acetylglucosaminidase, OGlcNAcase. J Biol Chem. 2002;277(3):1755–1761.
  • Hanover JA, Krause MW, Love DC. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol. 2012;13(5):312–321.
  • Bond MR, Hanover JA. A little sugar goes a long way: the cell biology of O-Glc NAc. J Cell Biol. 2015;208(7):869–880.
  • Müller R, Jenny A, Stanley P. The EGF repeat-specific O-GlcNAc-transferase Eogt interacts with notch signaling and pyrimidine metabolism pathways in Drosophila. PLoS ONE. 2013;8(5):e62835.
  • Drougat L, Olivier-Van Stichelen S, Mortuaire M, et al. Characterization of O-GlcNAc cycling and proteomic identification of differentially O-GlcNAcylated proteins during G1/S transition. Biochim Biophys Acta. 2012;1820 (12); 1839–1848.
  • Zachara NE, Hart GW. O-GlcNAc modification: a nutritional sensor that modulates proteasome function. Trends Cell Biol. 2004;14(5):218–221.
  • Vosseller K, Wells L, Lane MD, et al. Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3–L1 adipocytes. Proc Natl Acad Sci U S A. 2002;99(8):5313–5318.
  • Arias EB, Kim J, Cartee GD. Prolonged incubation in PUGNAc results in increased protein O-linked glycosylation and insulin resistance in rat skeletal muscle. Diabetes. 2004;53(4):921–930.
  • Lagerlöf O, Slocomb JE, Hong I, et al. The nutrient sensor OGT in PVN neurons regulates feeding. Science. 2016;351(6279):1293–1296.
  • Lehman DM, Fu D-J, Freeman AB, et al. A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-beta-D- Glucosaminidase is associated with Type 2 diabetes in Mexican Americans. Diabetes. 2005;54(4):1214–1221.
  • Ma J, Hart GW. Protein O-GlcNAcylation in diabetes and diabetic complications. Expert Rev Proteomics. 2013;10(4):365–380.
  • Zachara NE. The roles of O-linked β-N-acetylglucosamine in cardiovascular physiology and disease. Am J Physiol Heart Circ Physiol. 2012;302(10):H1905–H1918.
  • Ferrer CM, Sodi VL, Reginato MJ. O-GlcNacylation in cancer biology: linking metabolism and signaling. J Mol Biol. 2016;428(16):3282–3294.
  • Singh JP, Zhang K, Wu J, et al. O-GlcNAc signaling in cancer metabolism and epigenetics. Cancer Lett. 2015;356(2):244–250.
  • Yuzwa SA, Vocadlo DJ. OGlcNAc and neurodegeneration: biochemical mechanism and potential roles in Alzheimer’s disease and beyond. J Chem Soc Rev. 2014;43(19):6839–6858.
  • Ryan P, Xu M, Davey AK, et al. O-GlcNAc modification protects against protein misfolding and aggregation in neurodegenerative disease. ACS Chem Neurosci. 2019;10(5):2209–2221.
  • Roquemore EP, Chevrier MR, Cotter RJ, et al. Dynamic O-GlcNAcylation of the small heat shock protein αB-Crystallin†. Biochemistry. 1996;35(11):3578–3586.
  • Chou CF, Smith AJ, Omary MB. Characterization and dynamics of O-linked glycosylation of human cytokeratin 8 and 18. J Biol Chem. 1992;267(6):3901–3906.
  • Haltiwanger RS, Holt GD, Hart GW. Enzymatic addition of O-GlcNAc to nuclear and cytoplasmic proteins. Identification of a uridine diphospho-N-acetylglucosamine: peptideβ-N-acetylglucosaminyltransferase. J Biol Chem. 1990;265(5):2563–2568.
  • Kreppel L, Blomberg M, Hart G. Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetra-tricopeptide repeats. J Biol Chem. 1997;272(14):9308–9315.
  • Lubas W, Frank D, Krause M, et al. O-Linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J Biol Chem. 1997;272(14):9316–9324.
  • Braidman I, Carroll M, Dance N, et al. Characterisation of human N-acetyl-β-hexosaminadase C. FEBS Lett. 1974;41(2):181–184.
  • Dong DL, Hart GW. Purification and characterization of an OglcNAc selective N-acetyl-β-D-glucosaminidase from rat spleen cytosol. J Biol Chem. 1994;269(30):19321–19330.
  • Heckel D, Comtesse N, Brass N, et al. Novel immunogenic antigen homologous to hyaluronidase in meningioma. Hum Mol Genet. 1998;7(12); 1859–1872.
  • Ma J, Hart GW. O-GlcNAc profiling: from proteins to proteomes. Clin Proteomics. 2014;11(1):8.
  • Vocadlo DJ. O-GlcNAc processing enzymes: catalytic mechanisms, substrate specificity, and enzyme regulation. Curr Opin Chem Biol. 2012;16(5–6):488–497.
  • Comtesse N, Maldener E, Meese E. Identification of a nuclear variant of MGEA5, a cytoplasmic hyaluronidase and a beta-N-acetylglucosaminidase. Biochem Biophys Res Commun. 2001;283(3):634–640.
  • Schimpl M, Schüttelkopf AW, Borodkin VS, et al. Human OGA binds substrates in a conserved peptide recognition groove. Biochem J. 2010;432(1–7):2010.
  • Rao FV, Dorfmueller HC, Villa F, et al. Insights into the mechanism and inhibition of eukaryotic O-GlcNAc hydrolysis. EMBO J. 2006;25(7):1569–1578.
  • Macauley MS, Whitworth GE, Debowski AW, et al. O-GlcNAcase uses substrate-assisted catalysis: kinetic analysis and development of highly selective mechanism-inspired inhibitors. J Biol Chem. 2005;280(27):25313–25322.
  • Cetinbas N, Macauley MS, Stubbs KA, et al. Identification of Asp 174 and Asp 175 as the key catalytic residues of human O-GlcNAcase by functional analysis of site-directed mutants. Biochemistry. 2006;45(11):3835–3844.
  • Herr R, Jahnke HK, Argoudelis AD. Structure of streptozotocin. J Am Chem Soc. 1967;89(18):4808–4809.
  • Roos MD, Xie W, Su K. et al. Streptozotocin, an analog of N-acetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins. Proc Assoc Am Physicians. 1998;110(5):422–432.
  • Gao Y, Parker GJ, Hart GW. Streptozotocin-induced beta-cell death is independent of its inhibition of O-GlcNAcase in pancreatic Min6 cells. Arch Biochem Biophys. 2000;383(2):296–302.
  • Horsch M, Hoesch L, Vasella A, et al. N-acetylglucosaminono-1,5-lactone oxime and the corresponding (phenylcarbamoyl)oxime. Novel and potent inhibitors of beta-N-acetylglucosaminidase. Eur J Biochem. 1991;197(3):815–818.
  • Vocadlo DJ, Gao Z, Gao Z, et al. NAG-thiazoline, An N-Acetyl-β-hexosaminidase inhibitor that implicates acetamido participation. J Am Chem Soc. 1996;118(28):6804–6805.
  • Whitworth GE, Macauley MS, Stubbs KA, et al. Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: mechanistic and structural insights into inhibitor selectivity and transition state poise. J Am Chem Soc. 2007;129(3):635–644.
  • Yuzwa SA, Macauley MS, Heinonen JE, et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol. 2008;4(8):483.
  • Dorfmueller HC, Borodkin VS, Schimpl M, et al. GlcNAcstatin: a picomolar, selective O-GlcNAcase inhibitor that modulates intracellular O-GlcNAcylation levels. J Am Chem Soc. 2006;128(51):16484–16485.
  • Bergeron-Brlek M, Goodwin-Tindall J, Cekic N, et al. A convenient approach to stereoisomeric iminocyclitols: generation of potent brain-permeable OGA inhibitors. Angew Chem Int Ed. 2015;54(51):15429–15433.
  • Elsen NL, Patel SB, Ford RE, et al. Insights into activity and inhibition from the crystal structure of human OGlcNAcase. Nat Chem Biol. 2017;13(6):613–615.
  • Roth C, Chan S, Offen WA, et al. Structural and functional insight into human O-GlcNAcase. Nat Chem Biol. 2017;13(6):610–612.
  • Li B, Li H, Lu L, et al. Structures of human OGlcNAcase and its complexes reveal a new substrate recognition mode. Nat Struct Mol Biol. 2017;24(4):362–369.
  • Akimoto Y, Comer FI, Cole RN, et al. Localization of the O-GlcNAc transferase and O-GlcNAc- modified proteins in rat cerebellar cortex. Brain Res. 2003;966(2):194–205.
  • Liu K, Paterson AJ, Zhang F, et al. Accumulation of protein O-GlcNAc modification inhibits proteasomes in the brain and coincides with neuronal apoptosis in brain areas with high O-GlcNAc metabolism. J Neurochem. 2004;89(4):1044–1055.
  • Liu Y, Li X, Yu Y, et al. Developmental regulation of protein O-GlcNAcylation, O-GlcNAc transferase, and O-GlcNAcase in mammalian brain. PLoS ONE. 2012;7(8):e43724.
  • Khidekel N, Ficarro SB, Peters EC, et al. Exploring the O-GlcNAc proteome: direct identification of O-GlcNAc-modified proteins from the brain. Proc Natl Acad Sci U.S.A. 2004;101(36):13132–13137.
  • Lagerlöf O. O-GlcNAc cycling in the developing, adult and geriatric brain. J Bioenerg Biomembr. 2018;50:241–261.
  • Marshall S, Bacote V, Traxinger RR. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem. 1991;266(8):4706–4712.
  • Liu F, Iqbal K, Grundke-Iqbal I, et al. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci U.S.A. 2004;101(29):10804–10809.
  • Jack CR, Knopman DS, Jagust WJ, et al. Update on hypothetical model of Alzheimer’s disease biomarkers. Lancet Neurol. 2013;12(2):207–216.
  • Iqbal K, Liu F, Gong C-X. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol. 2016;12:15–27.
  • Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24(1):1121–1159.
  • Arnold CS, Johnson GVW, Cole RN, et al. The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J Biol Chem. 1996;271(46):28741–28744.
  • Liu F, Shi J, Tanimukai H, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain. 2009;132(7):1820–1832.
  • Yuzwa SA, Vocadlo DJ. O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer’s disease and beyond. Chem Soc Rev. 2014;43(19):6839–6858.
  • Yuzwa SA, Shan X, Macauley MS, et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012;8(4):393–399.
  • Hart GW, Slawson C, Ramirez-Correa G, et al. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 2011;80(1):825–858.
  • van der Laarse SAM, Leney AC, Heck AJR. Crosstalk between phosphorylation and O-Glc NA cylation: friend or foe. FEBS J. 2018;285(17):3152–3167.
  • Di Domenico F, Lanzillotta C, Tramutola A. Therapeutic potential of rescuing protein O-GlcNAcylation in tau-related pathologies. Expert Rev Neurother. 2019;19(1):1–3.
  • Yuzwa SA, Shan X, Macauley MS, et al. Increasing O-GlNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012;8(4):393–399.
  • Yuzwa SA, Macauley MS, Heinonen JE, et al. Apotent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol. 2008;4(8):483–490.
  • Graham DL, Gray AJ, Joyce JA, et al. Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy. Neuropharmacology. 2014;79:307–313.
  • Hastings NB, Wang X, Song L, et al. Inhibition of O-GlcNacase leads to elevation of O-GlcNac tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener. 2017;12(1):39–55.
  • Wang X, Smith K, Pearson M, et al. Early intervention of Tau Pathology prevents behavioral changes in the rTg4510 mouse model of tauopathy. PLoS ONE. 2018;13(4):e0195486.
  • Wang X, Li W, Marcus J, et al. MK-8719, a novel and selective O-GlcNAcase inhibitor that reduces the formation of pathological tau and ameliorates neurodegeneration in a mouse model of tauopathy. J Pharmacol Exp Ther. 2020;374(2):252–263.
  • Borghgraef P, Menuet C, Theunis C, et al. Increasing brain protein O-GlcNAcylation mitigates breathing defects and mortality of tau P301L mice. PLoS ONE. 2013;8(12):e84442.
  • Medina M. An overview on the clinical development of tau-based therapeutics. Int J Mol Sci. 2018;19(4):1160–1173.
  • Selnick HG, Hess JF, Tang C, et al. Discovery of MK-8719, a potent O-GlcNAcase inhibitor as a potential treatment for tauopathies. J Med Chem. 2019;62(22):10062–10097.
  • Smith SM, Struyk A, Jonathan D, et al. Early clinical results and preclinical validation of the O-GlNAcase (OGA) inhibitor MK-8719 as a novel therapeutic for the treatment of tauopathies. Alzheimer´s & Dementia. 2016;12:261.
  • [cited 2020 Feb 5]. Available from:http://alectos.com/content/pipeline/.
  • Quattropani A, Hantson J, Hantson J, et al. Pharmacological intervention with the novel o-GlcNacase inhibitor ASN-561 reduces pathological tau in transgenic mice. Alzheimers Dement. 2015;11(7S_Part_5):227.
  • [cited 2020 Feb 12]. Available from:https://www.asceneuron.com/pipeline.
  • [cited 2020 Feb 12]. Available from:https://www.asceneuron.com/news.
  • [cited 2020 Feb 12]. Available from:https://clinicaltrials.gov/.
  • [cited 2020 Feb 12]. Available from:https://www.lilly.com/discovery/pipeline.
  • Paul S, Haskali MB, Liow JS, et al. Evaluation of a PET radioligand to image O-GlcNAcase in brain and periphery of Rhesus monkey and Knock-Out Mouse. J Nucl Med. 2019;60(1):129–134.
  • Vocadlo DJ, Mceachern EJ, Stubbs K, Selective glycosidase inhibitors and uses thereof. WO012106 (2010).
  • Vocadlo DJ, Mceachern EJ, Selective glycosidase inhibitors and uses thereof. WO037207 (2010).
  • Mceachern EJ, Sun J, Vocadlo DJ, et al. Glycosidase inhibitors and uses thereof. WO032185 (2014).
  • Mceachern EJ, Sun J, Vocadlo DJ, et al. Glycosidase inhibitors and uses thereof. WO032188 (2014).
  • Mceachern EJ, Vocadlo DJ, Zhou Y, et al. Glycosidase inhibitors and uses thereof WO032187 (2014).
  • The formula LE = (pIC50 x 1.37)/heavy atom count, was used.
  • Vocadlo DJ, Mceachern EJ, Selective glycosydase inhibitors and uses thereof, WO012107 (2010).
  • Tong-Shang LI, Mceachern EJ, Vocadlo DJ, et al. Selective glycosydase inhibitors and uses thereof, WO140640 (2011).
  • Li T-S, Mceachern EJ, Vocadlo DJ, et al. Selective glycosydase inhibitors and uses thereof, WO000085 (2013).
  • Selnick HG, Liu K, Mceachern EJ, et al. Selective glycosydase inhibitors and uses thereof, WO025452 (2013).
  • Coburn C, Liu K, Mceachern EJ, et al. Selective glycosydase inhibitors and uses thereof, WO061927 (2012).
  • Coburn C, Liu K, Mceachern EJ, et al. Selective glycosydase inhibitors and uses thereof, WO061971 (2012).
  • Kaul R, Mceachern EJ, Vocadlo DJ, et al. Selective glycosidase inhibitors and uses thereof, WO129651 (2012).
  • Kaul R, Mceachern EJ, Mu C, et al. Selective glycosydase inhibitors and uses thereof, WO083435 (2012). Data differs from the recently published work by the Alectos Therapeutics and Merck Sharp and Dohme scientists in. J Med Chem. 2019;62(22):10062–10097.
  • Tong-Shuang LI, Mceachern EJ, Vocadlo DJ, et al. Selective glycosidase inhibitors and uses thereof, WO000086 (2013).
  • Kaul R, Mceachern EJ, Vocadlo DJ, et al. Glycosidase inhibitors and uses thereof, WO067003 (2014).
  • Liu K, Mceachern EJ, Mu C, et al. Selective glycosidase inhibitors and uses thereof, WO061972 (2012).
  • Chang J, Liu K, Mceachern EJ et al. Pyrano[3,2-d]thiazol derivatives and uses thereof as elective glycosidase inhibitors, WO062157 (2012).
  • Chang J, Liu K, Mceachern EJ, et al. Selective glycosidase inhibitors and uses thereof, WO064680 (2012).
  • Mceachern EJ, Vocadlo DJ, Zhou Y, et al. Selective glycosidase inhibitors and uses thereof, WO126091 (2012).
  • Selnick HG, Li W, Hostetler E, et al. Permeable glycosidase inhibitors and uses thereof, WO168576 (2013).
  • Hg S, Li W, Hostetler E, et al. Permeable glycosidase inhibitors and uses thereof, WO166654 (2013).
  • Selnick HG, Liu K, Kaul R et al. Selective glycosidase inhibitors and uses thereof, WO100934 (2014).
  • Vocadlo D, Mceachern EJ, Withworth G, Selective glycosidase inhibitors and uses thereof, WO025170 (2008).
  • Mceachern EJ, Selnick HG, Zhou Y, Glycosidase inhibitors and uses thereof, WO106254 (2017).
  • Donnely M, Qiu H, Yu H et al., Pyrano[3,2-d][1,3]thiazole as glycosidase inhibitors, WO028715 (2013).
  • Yu H, Liu-Bujalski L, Johnson TL, Glycosidase inhibitors, WO159234 (2014).
  • [cited 2021 May 04]. Available from:https://www.asceneuron.com/mission-history.
  • Quattropanni A, Kulkarni S, Giri AG, Glycosidase inhibitors, WO030443 (2016).
  • Quattropanni A, Kulkarni S, Giri AG, Glycosidase inhibitors, WO144633 (2017); (b) Quattropanni A, Kulkarni S, Giri AG, Glycosidase inhibitors, WO144639 (2017).
  • Quattropanni A, Kulkarni S, Giri AG, et al. Process for the separation of enantiomers of piperazine derivatives, IN21006637 (2016).
  • Quattropanni A, Kulkarni S, Giri AG, et al., Acid addition salts of piperazine derivatives, WO144637 (2017).
  • Quattropanni A, Kulkarni S, Giri AG, Substituted dihydrobenzofurane glycosidase inhibitors, WO153507 (2018).
  • Quattropanni A, Kulkarni S, Giri AG, Sulfoximine glycosidase inhibitors, WO153508 (2018).
  • Quattropanni A, Kulkarni S, Giri AG, Annulated glycosidase inhibitors, WO037861 (2019).
  • Quatroppani A, Wishart G, Kulkarni S et al. Pyrrolidine glycosidase inhibitors. WO039027 (2020).
  • Quatroppani A, Wishart G, Kulkarni S, et al. Tetrahydro-benzoazepine glycosidase inhibitors. WO039028 (2020).
  • Quatroppani A, Kulkarni S, Rakesh P, et al. Spirocompounds as glycosidase inhibitors. WO039029 (2020).
  • Quatroppani A, Kulkarni S, Rakesh P Fused glycosidase inhibitors. WO169804 (2020).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Martínez Viturro CM, et al. Bicyclic OGA inhibitor compounds. WO109198 (2018).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Alcázar-Vaca MJ [1,2,4]Triazolo[1,5-a]pyrimidinyl derivatives substituted with piperidine, morpholine or piperazine as OGA inhibitors and their preparation. WO154133 (2018).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Alcázar-Vaca MJ, et al. Monocyclic OGA inhibitor compounds. WO109202 (2018).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Martínez Viturro CM, et al. Bicyclic OGA inhibitor compounds. WO141984 (2018).
  • Martínez-Viturro CM, Trabanco AA, Royes J, et al. Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders. J Med Chem. 2020;63(22):14017–14044.
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Martínez Viturro CM, et al. Bicyclic OGA inhibitor compounds. WO243526 (2019).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Martínez Viturro CM OGA inhibitor compounds. WO243525 (2019).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, De Lucas-Olivares AI, et al. OGA inhibitor compounds. WO243528 (2019).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Delgado-Jiménez F, et al. OGA inhibitor compounds. WO243531 (2019).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Martínez Viturro CM, et al. Bicyclic OGA inhibitor compounds. WO243527 (2019).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, De Lucas-Olivares AI, et al. OGA inhibitor compounds. WO243530 (2019).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Leenaerts JE, et al. OGA inhibitor compounds. WO243533 (2019).
  • Bartolomé-Nebreda JM, Trabanco-Suárez AA, Tresadern GJ, et al. OGA inhibitor compounds. WO243535 (2019).
  • Dreyfus NJF, Lindsay-Scott PJ, N-[4-Fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide as OGA inhibitor. WO140299 (2018).
  • NJF D, Lindsay-Scott PJ, Rathmell RE, 5-Methyl-1,3,4-oxadiazol-2-yl compounds. WO217588 (2018).
  • NJF D, Faller A, 2,3-Dihydrofuro[2,3-b]pyridine compounds. WO245907 (2019).
  • Dreyfus NJF, Lindsay-Scott PJ, 5-Methyl-4-fluoro-thiazol-2-yl compounds. WO028115 (2020).
  • Dreyfus NJF, Lopez JE, Winneroski LL, et al. 6-Fluoro-2-methylbenzo[b]thiazol-5-yl compounds. WO068530 (2020).
  • Hayashi ML, Irizzary MC, Nuthall H, Combination Therapy. WO028141 (2020).
  • Genung N, Guckian KM, Vessels J, et al. O-Glycoprotein-2-acetamido-2-deoxy-3-D-glycopyranosidase inhibitors. WO178191 (2019).
  • Genung N, Guckian KM, Vessels J, et al. O-Glycoprotein-2-acetamido-2-deoxy-3-D-glycopyranosidase inhibitors. WO117961 (2020).
  • Genung N, Guckian KM, Vessels J, et al. Morpholinyl, piperazinyl, oxazepanyl and diazepanyl O-glycoprotein-2-acetamido-2-deoxy-3-D-glycopyranosidase inhibitors. WO061150 (2020).
  • Genung N, Guckian KM, Vessels J, et al. Bicyclic ether O-glycoprotein-2-acetamido-2-deoxy-3-D-glycopyranosidase inhibitors. WO163193 (2020).
  • Genung N, Guckian KM, Vessels J, et al. Azetidinyl O-glycoprotein-2-acetamido-2-deoxy-3-D-glycopyranosidase inhibitors. WO185593 (2020).
  • Storer R, Tinsley JM, Wilson FX et al. Pyrrolidine derivatives as selective glycosidase inhibitors and uses thereof. WO117219 (2012).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.