title: Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1.
abstract: Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aβ levels, but did not lower rat brain Aβ due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. lawrence.marcin@bms.com
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Marcin
authors.forename: Mendi A
authors.initials: MA
authors.lastname: Higgins
authors.forename: F Christopher
authors.initials: FC
authors.lastname: Zusi
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michael F
authors.initials: MF
authors.lastname: Dee
authors.forename: Michael F
authors.initials: MF
authors.lastname: Parker
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Muckelbauer
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Camac
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.forename: Vidhyashankar
authors.initials: V
authors.lastname: Ramamurthy
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.forename: James E
authors.initials: JE
authors.lastname: Grace
authors.forename: Jovita A
authors.initials: JA
authors.lastname: Marcinkeviciene
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kopcho
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Burton
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D016229:Amyloid beta-Peptides; D007211:Indoles; D011480:Protease Inhibitors; D011725:Pyridines; C030374:indole; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat