title: Discovery of cyclic sulfone hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid β-peptides.
abstract: Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.
authors.affiliation: Department of Global Discovery Chemistry, Institutes for BioMedical Research, Novartis Pharma AG, CH-4057 Basel, Switzerland. heinrich.rueeger@novartis.com
authors.forename: Heinrich
authors.initials: H
authors.lastname: Rueeger
authors.forename: Rainer
authors.initials: R
authors.lastname: Lueoend
authors.forename: Olivier
authors.initials: O
authors.lastname: Rogel
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
authors.forename: Henrik
authors.initials: H
authors.lastname: Möbitz
authors.forename: Rainer
authors.initials: R
authors.lastname: Machauer
authors.forename: Laura
authors.initials: L
authors.lastname: Jacobson
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C574648:3-(4-amino-3-fluoro-5-((1,1,1-trifluoro-3-methoxypropan-2-yl)oxy)benzyl)-5-((3-(tert-butyl)benzyl)amino)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide; C574647:3-(4-amino-3-fluoro-5-(2,2,2-trifluoroethoxy)benzyl)-5-((3-(tert-butyl)benzyl)amino)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide; D016229:Amyloid beta-Peptides; D001555:Benzene Derivatives; D003499:Cyclic S-Oxides; D005021:Ethylamines; D007191:Indazoles; D007211:Indoles; D013141:Spiro Compounds; D013450:Sulfones; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse