title: Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor.
abstract: According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dean
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lowe
authors.forename: Ferenc
authors.initials: F
authors.lastname: Martenyi
authors.forename: Scott M
authors.initials: SM
authors.lastname: Sheehan
authors.forename: Leonard N
authors.initials: LN
authors.lastname: Boggs
authors.forename: Scott A
authors.initials: SA
authors.lastname: Monk
authors.forename: Brian M
authors.initials: BM
authors.lastname: Mathes
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Mergott
authors.forename: Brian M
authors.initials: BM
authors.lastname: Watson
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Stout
authors.forename: David E
authors.initials: DE
authors.lastname: Timm
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smith Labell
authors.forename: Celedon R
authors.initials: CR
authors.lastname: Gonzales
authors.forename: Masako
authors.initials: M
authors.lastname: Nakano
authors.forename: Stanford S
authors.initials: SS
authors.lastname: Jhee
authors.forename: Mark
authors.initials: M
authors.lastname: Yen
authors.forename: Larry
authors.initials: L
authors.lastname: Ereshefsky
authors.forename: Terry D
authors.initials: TD
authors.lastname: Lindstrom
authors.forename: David O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Cocke
authors.forename: D
authors.initials: D
authors.lastname: Greg Hall
authors.forename: Stuart
authors.initials: S
authors.lastname: Friedrich
authors.forename: Martin
authors.initials: M
authors.lastname: Citron
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003461:Crystallography / Q000379:methods; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008956:Models, Chemical; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; C569204:LY2811376; D010446:Peptide Fragments; D011743:Pyrimidines; D013843:Thiazines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human
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