title: Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.
abstract: This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aβ levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aβ levels were not obtained.
authors.affiliation: Bristol-Myers Squibb Research, 5 Research Parkway, Wallingford, Connecticut 06492, United States. samuel.gerritz@bms.com
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Gerritz
authors.forename: Weixu
authors.initials: W
authors.lastname: Zhai
authors.forename: Shuhao
authors.initials: S
authors.lastname: Shi
authors.forename: Shirong
authors.initials: S
authors.lastname: Zhu
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Iben
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Burton
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Muckelbauer
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Camac
authors.forename: William
authors.initials: W
authors.lastname: Metzler
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Cook
authors.forename: Ramesh
authors.initials: R
authors.lastname: Padmanabha
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sofia
authors.forename: Michael A
authors.initials: MA
authors.lastname: Poss
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D054852:Small Molecule Libraries; D060327:Solid-Phase Synthesis Techniques; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006146:Guanidines; D007555:Isoxazoles; D010446:Peptide Fragments; D054852:Small Molecule Libraries; D012996:Solutions; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human