title: Discovery of potent iminoheterocycle BACE1 inhibitors.
abstract: The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aβ40 levels upon subcutaneous and oral administration to rats.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: john.caldwell@merck.com.
authors.forename: John P
authors.initials: JP
authors.lastname: Caldwell
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Mazzola
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: James
authors.initials: J
authors.lastname: Durkin
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Favreau
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kennedy
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Reshma
authors.initials: R
authors.lastname: Kuvelkar
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Nansie
authors.initials: N
authors.lastname: McHugh
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: McKittrick
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stamford
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Voigt
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Liyang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D015195:Drug Design; D055808:Drug Discovery; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; Aspartyl protease inhibitors; BACE; Structure-based drug design; β-Secretase