title: Creation of Novel Cores for β-Secretase (BACE-1) Inhibitors: A Multiparameter Lead Generation Strategy.
abstract: In order to find optimal core structures as starting points for lead optimization, a multiparameter lead generation workflow was designed with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. De novo design of core fragments was connected with three predictive in silico models addressing target affinity, permeability, and hERG activity, in order to guide synthesis. Taking advantage of an additive SAR, the prioritized cores were decorated with a few, well-characterized substituents from known BACE-1 inhibitors in order to allow for core-to-core comparisons. Prediction methods and analyses of how physicochemical properties of the core structures correlate to in vitro data are described. The syntheses and in vitro data of the test compounds are reported in a separate paper by Ginman et al. [J. Med. Chem. 2013, 56, 4181-4205]. The affinity predictions are described in detail by Roos et al. [J. Chem. Inf. 2014, DOI: 10.1021/ci400374z].
authors.affiliation: Department of Medicinal Chemistry AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Viklund
authors.affiliation: Department of Medicinal Chemistry AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Kolmodin
authors.affiliation: Department of Medicinal Chemistry AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nordvall
authors.affiliation: Department of Medicinal Chemistry AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.affiliation: Department of Medicinal Chemistry AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Svensson
authors.affiliation: Department of Medicinal Chemistry AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden.
authors.forename: Ylva
authors.initials: Y
authors.lastname: Gravenfors
authors.affiliation: Department of Medicinal Chemistry AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Rahm
keywords: BACE-1 inhibitor; core optimization; fragment optimization; multiparameter optimization; scaffold hopping; β-secretase inhibitor