title: Structure based design of iminohydantoin BACE1 inhibitors: identification of an orally available, centrally active BACE1 inhibitor.
abstract: From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
authors.affiliation: Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. jared.cumming@merck.com
authors.forename: Jared N
authors.initials: JN
authors.lastname: Cumming
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Smith
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Misiaszek
authors.forename: James
authors.initials: J
authors.lastname: Durkin
authors.forename: Jianping
authors.initials: J
authors.lastname: Pan
authors.forename: Ulrich
authors.initials: U
authors.lastname: Iserloh
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Zhu
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.forename: Johannes
authors.initials: J
authors.lastname: Voigt
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Kennedy
authors.forename: Reshma
authors.initials: R
authors.lastname: Kuvelkar
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.forename: Kathleen
authors.initials: K
authors.lastname: Cox
authors.forename: Leonard
authors.initials: L
authors.lastname: Favreau
authors.forename: Michael F
authors.initials: MF
authors.lastname: Czarniecki
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Brian A
authors.initials: BA
authors.lastname: McKittrick
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000097:blood / Q000134:cerebrospinal fluid; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D006827:Hydantoins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat