title: A conformational constraint improves a beta-secretase inhibitor but for an unexpected reason.
abstract: During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., West Point, PA 19486, USA. ivory_hills@merck.com
authors.forename: Ivory D
authors.initials: ID
authors.lastname: Hills
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Pablo
authors.initials: P
authors.lastname: de León
authors.forename: Ashley
authors.initials: A
authors.lastname: Nomland
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Hemaka
authors.initials: H
authors.lastname: Rajapakse
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Allison
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pietrak
authors.forename: Dawn
authors.initials: D
authors.lastname: Toolan
authors.forename: Sharie J
authors.initials: SJ
authors.lastname: Haugabook
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007093:Imidazoles; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases