Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer’s disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before developme...

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Published in	Journal of medicinal chemistry Vol. 64; no. 12; pp. 8076 - 8100
Main Authors	McKinzie, David L, Winneroski, Leonard L, Green, Steven J, Hembre, Erik J, Erickson, Jon A, Willis, Brian A, Monk, Scott A, Aluise, Christopher D, Baker, Thomas K, Lopez, Jose E, Hendle, Jörg, Beck, James P, Brier, Richard A, Boggs, Leonard N, Borders, Anthony R, Cocke, Patrick J, Garcia-Losada, Pablo, Lowe, Stephen L, Mathes, Brian M, May, Patrick C, Porter, Warren J, Stout, Stephanie L, Timm, David E, Watson, Brian M, Yang, Zhixiang, Mergott, Dustin J
Format	Journal Article
Language	English
Published	WASHINGTON American Chemical Society 24.06.2021 Amer Chemical Soc
Subjects	Chemistry, Medicinal Life Sciences & Biomedicine Pharmacology & Pharmacy Science & Technology BETA-SECRETASE IN-VITRO ALZHEIMERS-DISEASE MUTATION LYSOSOMAL STORAGE OPTIMIZATION MICE AMYLOID PRECURSOR PROTEIN CLEAVAGE CATHEPSIN-D DEFICIENCY
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Abstract	The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer’s disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.
AbstractList	The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges. The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.
Author	Mathes, Brian M Porter, Warren J Winneroski, Leonard L Garcia-Losada, Pablo Lowe, Stephen L Yang, Zhixiang Hembre, Erik J Lopez, Jose E Watson, Brian M Beck, James P Aluise, Christopher D Borders, Anthony R Baker, Thomas K Hendle, Jörg Erickson, Jon A Green, Steven J Stout, Stephanie L McKinzie, David L Cocke, Patrick J Timm, David E Boggs, Leonard N Brier, Richard A Willis, Brian A May, Patrick C Monk, Scott A Mergott, Dustin J
AuthorAffiliation	A Division of Eli Lilly and Company Department of Biochemistry Lilly Research Laboratories
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Cites_doi	10.1021/acs.jmedchem.8b00246 10.1038/990114 10.1021/jm301039c 10.1021/acs.jmedchem.5b01101 10.1038/990107 10.1016/j.bmc.2019.115194 10.1111/jnc.12715 10.1126/science.290.5489.150 10.1124/dmd.108.025064 10.1093/emboj/19.12.2786 10.1056/NEJMoa1812840 10.1177/0192623314553804 10.1016/j.bmcl.2018.12.049 10.1016/j.tins.2016.01.003 10.1002/hep.22272 10.1038/nrneurol.2009.218 10.1007/s40263-018-0598-1 10.1523/JNEUROSCI.3647-11.2011 10.1523/JNEUROSCI.20-18-06898.2000 10.1080/13543784.2019.1683160 10.1016/j.biopsych.2020.02.001 10.1111/j.1471-4159.2004.02764.x 10.1016/j.jalz.2016.06.791 10.1002/ana.24969 10.1016/j.bmcl.2020.127503 10.1086/504159 10.1177/1087057104272295 10.14283/jpad.2019.3 10.1021/acs.jmedchem.5b01995 10.1242/jcs.02447 10.1078/0940-2993-00338 10.1016/j.trci.2019.02.005 10.1038/ncomms13042 10.1016/S1474-4422(19)30480-6 10.1021/mp300555n 10.1021/bi100637n 10.1021/acs.oprd.9b00471 10.1001/jamaneurol.2019.3988 10.3389/fnmol.2017.00097 10.1038/nature11283 10.1002/jcc.24719 10.1080/13543776.2021.1832463 10.1126/science.286.5440.735 10.1021/jm400225m 10.1523/JNEUROSCI.4129-14.2015 10.3233/ADR-210296 10.1016/j.jala.2005.05.002 10.1006/mcne.1999.0811 10.1101/cshperspect.a006262 10.1002/jps.22452
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References	ref9/cit9 ref45/cit45 ref3/cit3 ref27/cit27 ref16/cit16 ref52/cit52 ref23/cit23 ref8/cit8 ref31/cit31 ref2/cit2 ref34/cit34 ref37/cit37 ref20/cit20 ref48/cit48 ref17/cit17 ref10/cit10 ref35/cit35 ref19/cit19 ref21/cit21 ref42/cit42 ref46/cit46 ref49/cit49 ref13/cit13 ref24/cit24 ref38/cit38 ref50/cit50 ref6/cit6 ref36/cit36 ref18/cit18 ref11/cit11 ref25/cit25 ref29/cit29 ref32/cit32 ref39/cit39 ref5/cit5 ref51/cit51 ref43/cit43 ref28/cit28 ref40/cit40 ref26/cit26 ref12/cit12 ref15/cit15 ref41/cit41 ref22/cit22 ref33/cit33 ref4/cit4 ref30/cit30 ref47/cit47 ref1/cit1 Ho N. F. H. (ref53/cit53) 2000 ref44/cit44 ref7/cit7 Zuhl, AM (WOS:000385551400001) 2016; 7 Vassar, R (WOS:000461790700001) 2019; 6 Dominguez, JL (WOS:000281052600003) 2010; 49 Masters, CL (WOS:000314278600001) 2012; 2 O'Neill, BT (WOS:000433403600015) 2018; 61 Steinfeld, R (WOS:000237553800008) 2006; 78 Hilpert, H (WOS:000319650100017) 2013; 56 Garcia-Losada, P (WOS:000516666200021) 2020; 24 Ellis, CR (WOS:000399970200016) 2017; 38 May, PC (WOS:000297215200003) 2011; 31 De Strooper, B (WOS:000275058300007) 2010; 6 Vassar, R (WOS:000337952800003) 2014; 130 Imbimbo, BP (WOS:000493127900001) 2019; 28 Desai, PV (WOS:000317094100011) 2013; 10 Sinha, S (WOS:000084013200058) 1999; 402 Willis, B. A. (000668340800010.31) 2016; 12 Mandal, M (WOS:000310769500026) 2012; 55 Ploemen, JPHTM (WOS:000220742100004) 2004; 55 Gonzalez-Polo, RA (WOS:000231204700010) 2005; 118 Dubin, AE (WOS:000227690100008) 2005; 10 May, PC (WOS:000349411700031) 2015; 35 Martiskainen, H (WOS:000406211100013) 2017; 82 Jonsson, T (WOS:000307010700040) 2012; 488 Yang, HC (WOS:000226115900001) 2004; 91 Barao, S (WOS:000371942200004) 2016; 39 Rafii, MS (WOS:000458497400001) 2019; 33 Egan, MF (WOS:000464610000008) 2019; 380 Vassar, R (WOS:000083303200044) 1999; 286 Patel, NC (WOS:000595163500005) 2020; 30 Zhao, R (WOS:000266147500015) 2009; 37 Hampel, H (WOS:000632814400007) 2021; 89 Ho, NFH (CCC:000084870200008) 2000; 102 Lammert, C (WOS:000256391500027) 2008; 47 Zamek-Gliszczynski, MJ (WOS:000289442200044) 2011; 100 Ly, J. Q. (000668340800010.29) 2005; 10 Yan, RQ (WOS:000401412600001) 2017; 10 Hsiao, CC (WOS:000458623500001) 2019; 29 Wessels, AM (WOS:000514922200010) 2020; 77 Hong, L (WOS:000089724800056) 2000; 290 Lopez, CL (WOS:000737696700001) 2019; 5 Lo, AC (WOS:000651079100033) 2021; 5 Rombouts, F (WOS:000599400200001) 2021; 31 Koike, M (WOS:000089379000020) 2000; 20 Schneider, L (WOS:000508351900013) 2020; 19 Tyynela, J (WOS:000087908900003) 2000; 19 Patterson, C. (000668340800010.1) 2018 Rombouts, FJR (WOS:000363915600022) 2015; 58
References_xml	– ident: ref22/cit22 doi: 10.1021/acs.jmedchem.8b00246 – ident: ref36/cit36 doi: 10.1038/990114 – ident: ref12/cit12 doi: 10.1021/jm301039c – ident: ref24/cit24 doi: 10.1021/acs.jmedchem.5b01101 – ident: ref38/cit38 doi: 10.1038/990107 – ident: ref11/cit11 doi: 10.1016/j.bmc.2019.115194 – ident: ref2/cit2 doi: 10.1111/jnc.12715 – ident: ref34/cit34 doi: 10.1126/science.290.5489.150 – ident: ref52/cit52 doi: 10.1124/dmd.108.025064 – ident: ref19/cit19 doi: 10.1093/emboj/19.12.2786 – ident: ref42/cit42 doi: 10.1056/NEJMoa1812840 – ident: ref15/cit15 doi: 10.1177/0192623314553804 – ident: ref5/cit5 doi: 10.1016/j.bmcl.2018.12.049 – ident: ref43/cit43 doi: 10.1016/j.tins.2016.01.003 – ident: ref10/cit10 doi: 10.1002/hep.22272 – ident: ref4/cit4 doi: 10.1038/nrneurol.2009.218 – ident: ref6/cit6 doi: 10.1007/s40263-018-0598-1 – ident: ref8/cit8 doi: 10.1523/JNEUROSCI.3647-11.2011 – ident: ref17/cit17 doi: 10.1523/JNEUROSCI.20-18-06898.2000 – ident: ref7/cit7 doi: 10.1080/13543784.2019.1683160 – ident: ref40/cit40 doi: 10.1016/j.biopsych.2020.02.001 – ident: ref49/cit49 doi: 10.1111/j.1471-4159.2004.02764.x – ident: ref32/cit32 doi: 10.1016/j.jalz.2016.06.791 – ident: ref47/cit47 doi: 10.1002/ana.24969 – ident: ref31/cit31 doi: 10.1016/j.bmcl.2020.127503 – ident: ref18/cit18 doi: 10.1086/504159 – ident: ref29/cit29 doi: 10.1177/1087057104272295 – ident: ref48/cit48 doi: 10.14283/jpad.2019.3 – ident: ref13/cit13 doi: 10.1021/acs.jmedchem.5b01995 – ident: ref21/cit21 doi: 10.1242/jcs.02447 – ident: ref25/cit25 doi: 10.1078/0940-2993-00338 – ident: ref41/cit41 doi: 10.1016/j.trci.2019.02.005 – ident: ref1/cit1 – ident: ref16/cit16 doi: 10.1038/ncomms13042 – ident: ref39/cit39 doi: 10.1016/S1474-4422(19)30480-6 – ident: ref51/cit51 doi: 10.1021/mp300555n – ident: ref26/cit26 doi: 10.1021/bi100637n – ident: ref28/cit28 doi: 10.1021/acs.oprd.9b00471 – ident: ref44/cit44 doi: 10.1001/jamaneurol.2019.3988 – ident: ref45/cit45 doi: 10.3389/fnmol.2017.00097 – start-page: 219 volume-title: Transport Processes in Pharmaceutical Systems year: 2000 ident: ref53/cit53 – ident: ref46/cit46 doi: 10.1038/nature11283 – ident: ref20/cit20 doi: 10.1002/jcc.24719 – ident: ref27/cit27 doi: 10.1080/13543776.2021.1832463 – ident: ref37/cit37 doi: 10.1126/science.286.5440.735 – ident: ref23/cit23 doi: 10.1021/jm400225m – ident: ref9/cit9 doi: 10.1523/JNEUROSCI.4129-14.2015 – ident: ref33/cit33 doi: 10.3233/ADR-210296 – ident: ref30/cit30 doi: 10.1016/j.jala.2005.05.002 – ident: ref35/cit35 doi: 10.1006/mcne.1999.0811 – ident: ref3/cit3 doi: 10.1101/cshperspect.a006262 – ident: ref50/cit50 doi: 10.1002/jps.22452 – volume: 2 start-page: ARTN a006262 year: 2012 ident: WOS:000314278600001 article-title: Biochemistry of Amyloid beta-Protein and Amyloid Deposits in Alzheimer Disease publication-title: COLD SPRING HARBOR PERSPECTIVES IN MEDICINE doi: 10.1101/cshperspect.a006262 – volume: 10 start-page: 225 year: 2005 ident: 000668340800010.29 article-title: Assessing hERG Channel Inhibition Using PatchXpress publication-title: JALA – volume: 130 start-page: 4 year: 2014 ident: WOS:000337952800003 article-title: Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects publication-title: JOURNAL OF NEUROCHEMISTRY doi: 10.1111/jnc.12715 – volume: 6 start-page: 78 year: 2019 ident: WOS:000461790700001 article-title: Implications for BACE1 Inhibitor Clinical Trials: Adult Conditional BACE1 Knockout Mice Exhibit Axonal Organization Defects in the Hippocampus publication-title: JPAD-JOURNAL OF PREVENTION OF ALZHEIMERS DISEASE doi: 10.14283/jpad.2019.3 – volume: 24 start-page: 306 year: 2020 ident: WOS:000516666200021 article-title: Synthesis, Optimization, and Large-Scale Preparation of the Low Dose Central Nervous System-Penetrant BACE1 Inhibitor LY3202626 via a [3+2] Nitrone Cycloaddition publication-title: ORGANIC PROCESS RESEARCH & DEVELOPMENT doi: 10.1021/acs.oprd.9b00471 – volume: 12 start-page: P418 year: 2016 ident: 000668340800010.31 article-title: Pharmacokinetics, pharmacodynamics, safety, and tolerability of LY3202626, a novel Bace1 inhibitor, in healthy subjects and patients with Alzheimer's disease publication-title: Alzheimer's Dementia – volume: 10 start-page: 168 year: 2005 ident: WOS:000227690100008 article-title: Identifying modulators of hERG channel activity using the PatchXpress((R)) planar patch clamp publication-title: JOURNAL OF BIOMOLECULAR SCREENING doi: 10.1177/1087057104272295 – volume: 5 start-page: 216 year: 2019 ident: WOS:000737696700001 article-title: The Alzheimer's Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer's disease publication-title: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS doi: 10.1016/j.trci.2019.02.005 – volume: 118 start-page: 3091 year: 2005 ident: WOS:000231204700010 article-title: The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death publication-title: JOURNAL OF CELL SCIENCE doi: 10.1242/jcs.02447 – volume: 488 start-page: 96 year: 2012 ident: WOS:000307010700040 article-title: A mutation in APP protects against Alzheimer's disease and age-related cognitive decline publication-title: NATURE doi: 10.1038/nature11283 – volume: 380 start-page: 1408 year: 2019 ident: WOS:000464610000008 article-title: Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease publication-title: NEW ENGLAND JOURNAL OF MEDICINE doi: 10.1056/NEJMoa1812840 – volume: 91 start-page: 1249 year: 2004 ident: WOS:000226115900001 article-title: Biochemical and kinetic characterization of BACE1: investigation into the putative species-specificity for beta- and beta '-cleavage sites by human and murine BACE1 publication-title: JOURNAL OF NEUROCHEMISTRY doi: 10.1111/j.1471-4159.2004.02764.x – volume: 7 start-page: ARTN 13042 year: 2016 ident: WOS:000385551400001 article-title: Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of beta-secretase inhibitors publication-title: NATURE COMMUNICATIONS doi: 10.1038/ncomms13042 – volume: 82 start-page: 128 year: 2017 ident: WOS:000406211100013 article-title: Decreased Plasma beta-Amyloid in the Alzheimer's Disease APP A673T Variant Carriers publication-title: ANNALS OF NEUROLOGY doi: 10.1002/ana.24969 – volume: 10 start-page: 1249 year: 2013 ident: WOS:000317094100011 article-title: Integration of in Silico and in Vitro Tools for Scaffold Optimization during Drug Discovery: Predicting P-Glycoprotein Efflux publication-title: MOLECULAR PHARMACEUTICS doi: 10.1021/mp300555n – volume: 38 start-page: 1260 year: 2017 ident: WOS:000399970200016 article-title: Conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor publication-title: JOURNAL OF COMPUTATIONAL CHEMISTRY doi: 10.1002/jcc.24719 – volume: 78 start-page: 988 year: 2006 ident: WOS:000237553800008 article-title: Cathepsin D deficiency is associated with a human neurodegenerative disorder publication-title: AMERICAN JOURNAL OF HUMAN GENETICS – volume: 37 start-page: 1251 year: 2009 ident: WOS:000266147500015 article-title: Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier publication-title: DRUG METABOLISM AND DISPOSITION doi: 10.1124/dmd.108.025064 – volume: 31 start-page: 16507 year: 2011 ident: WOS:000297215200003 article-title: Robust Central Reduction of Amyloid-beta in Humans with an Orally Available, Non-Peptidic beta-Secretase Inhibitor publication-title: JOURNAL OF NEUROSCIENCE doi: 10.1523/JNEUROSCI.3647-11.2011 – year: 2018 ident: 000668340800010.1 publication-title: World Alzheimer Report – volume: 10 start-page: ARTN 97 year: 2017 ident: WOS:000401412600001 article-title: Physiological Functions of the beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2 publication-title: FRONTIERS IN MOLECULAR NEUROSCIENCE doi: 10.3389/fnmol.2017.00097 – volume: 55 start-page: 9331 year: 2012 ident: WOS:000310769500026 article-title: Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/jm301039c – volume: 290 start-page: 150 year: 2000 ident: WOS:000089724800056 article-title: Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor publication-title: SCIENCE – volume: 100 start-page: 2498 year: 2011 ident: WOS:000289442200044 article-title: Validation of 96-well Equilibrium Dialysis with Non-radiolabeled Drug for Definitive Measurement of Protein Binding and Application to Clinical Development of Highly-Bound Drugs publication-title: JOURNAL OF PHARMACEUTICAL SCIENCES doi: 10.1002/jps.22452 – volume: 89 start-page: 745 year: 2021 ident: WOS:000632814400007 article-title: The beta-Secretase BACE1 in Alzheimer's Disease publication-title: BIOLOGICAL PSYCHIATRY doi: 10.1016/j.biopsych.2020.02.001 – volume: 35 start-page: 1199 year: 2015 ident: WOS:000349411700031 article-title: The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central A beta Pharmacodynamic Responses in Mice, Dogs, and Humans publication-title: JOURNAL OF NEUROSCIENCE doi: 10.1523/JNEUROSCI.4129-14.2015 – volume: 58 start-page: 8216 year: 2015 ident: WOS:000363915600022 article-title: 1,4-Oxazine beta-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.5b01101 – volume: 28 start-page: 967 year: 2019 ident: WOS:000493127900001 article-title: Investigational BACE inhibitors for the treatment of Alzheimer's disease publication-title: EXPERT OPINION ON INVESTIGATIONAL DRUGS doi: 10.1080/13543784.2019.1683160 – volume: 286 start-page: 735 year: 1999 ident: WOS:000083303200044 article-title: beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE publication-title: SCIENCE – volume: 29 start-page: 761 year: 2019 ident: WOS:000458623500001 article-title: New evolutions in the BACE1 inhibitor field from 2014 to 2018 publication-title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS doi: 10.1016/j.bmcl.2018.12.049 – volume: 47 start-page: 2003 year: 2008 ident: WOS:000256391500027 article-title: Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: Search for signals publication-title: HEPATOLOGY doi: 10.1002/hep.22272 – volume: 6 start-page: 99 year: 2010 ident: WOS:000275058300007 article-title: The secretases: enzymes with therapeutic potential in Alzheimer disease publication-title: NATURE REVIEWS NEUROLOGY doi: 10.1038/nrneurol.2009.218 – volume: 19 start-page: 111 year: 2020 ident: WOS:000508351900013 article-title: A resurrection of aducanumab for Alzheimer's disease publication-title: LANCET NEUROLOGY doi: 10.1016/S1474-4422(19)30480-6 – volume: 5 start-page: 321 year: 2021 ident: WOS:000651079100033 article-title: Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer's Disease Dementia publication-title: JOURNAL OF ALZHEIMERS DISEASE REPORTS doi: 10.3233/ADR-210296 – volume: 55 start-page: 347 year: 2004 ident: WOS:000220742100004 article-title: Use of physicochemical calculation of pKa and CLogP to predict phospholipidosis-inducing potential - A case study with structurally related piperazines publication-title: EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY – volume: 31 start-page: 25 year: 2021 ident: WOS:000599400200001 article-title: Small-molecule BACE1 inhibitors: a patent literature review (2011 to 2020) publication-title: EXPERT OPINION ON THERAPEUTIC PATENTS doi: 10.1080/13543776.2021.1832463 – volume: 61 start-page: 4476 year: 2018 ident: WOS:000433403600015 article-title: Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.8b00246 – volume: 39 start-page: 158 year: 2016 ident: WOS:000371942200004 article-title: BACE1 Physiolocical Functions May Limit Its Use as Therapeutic Tarcet for Alzneimer's Disease publication-title: TRENDS IN NEUROSCIENCES doi: 10.1016/j.tins.2016.01.003 – volume: 33 start-page: 99 year: 2019 ident: WOS:000458497400001 article-title: Alzheimer's Disease Clinical Trials: Moving Toward Successful Prevention publication-title: CNS DRUGS doi: 10.1007/s40263-018-0598-1 – volume: 19 start-page: 2786 year: 2000 ident: WOS:000087908900003 article-title: A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration publication-title: EMBO JOURNAL – volume: 402 start-page: 537 year: 1999 ident: WOS:000084013200058 article-title: Purification and cloning of amyloid precursor protein beta-secretase from human brain publication-title: NATURE – volume: 77 start-page: 199 year: 2020 ident: WOS:000514922200010 article-title: Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials publication-title: JAMA NEUROLOGY doi: 10.1001/jamaneurol.2019.3988 – volume: 20 start-page: 6898 year: 2000 ident: WOS:000089379000020 article-title: Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons publication-title: JOURNAL OF NEUROSCIENCE – volume: 102 start-page: 219 year: 2000 ident: CCC:000084870200008 article-title: Quantitative approaches to delineate passive transport mechanisms in cell culture monolayers publication-title: TRANSPORT PROCESSES IN PHARMACEUTICAL SYSTEMS – volume: 49 start-page: 7255 year: 2010 ident: WOS:000281052600003 article-title: Effect of the Protonation State of the Titratable Residues on the Inhibitor Affinity to BACE-1 publication-title: BIOCHEMISTRY doi: 10.1021/bi100637n – volume: 30 start-page: ARTN 127503 year: 2020 ident: WOS:000595163500005 article-title: Methods to optimize CNS exposure of drug candidates publication-title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS doi: 10.1016/j.bmcl.2020.127503 – volume: 56 start-page: 3980 year: 2013 ident: WOS:000319650100017 article-title: beta-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer's Disease publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/jm400225m
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Snippet	The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer’s disease drug target owing to its critical role in the production of... The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of...
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SubjectTerms	Chemistry, Medicinal Life Sciences & Biomedicine Pharmacology & Pharmacy Science & Technology
Title	Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor
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