title: Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.
abstract: We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).
authors.affiliation: Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, LLC, Spring House, PA 19477-0776, USA.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Huang
authors.forename: Eric D
authors.initials: ED
authors.lastname: Strobel
authors.forename: Chih Y
authors.initials: CY
authors.lastname: Ho
authors.forename: Charles H
authors.initials: CH
authors.lastname: Reynolds
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Conway
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Piesvaux
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Brenneman
authors.forename: George J
authors.initials: GJ
authors.lastname: Yohrling
authors.forename: H
authors.initials: H
authors.lastname: Moore Arnold
authors.forename: Daniel
authors.initials: D
authors.lastname: Rosenthal
authors.forename: Richard S
authors.initials: RS
authors.lastname: Alexander
authors.forename: Brett A
authors.initials: BA
authors.lastname: Tounge
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.forename: Marc
authors.initials: M
authors.lastname: Vandermeeren
authors.forename: Michael H
authors.initials: MH
authors.lastname: Parker
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.forename: Ellen W
authors.initials: EW
authors.lastname: Baxter
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011799:Quinazolines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human