title: Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates.
abstract: We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2″ pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aβ in nonrodent preclinical species.
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Mihirbaran
authors.initials: M
authors.lastname: Mandal
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Misiaszek
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Alexei
authors.initials: A
authors.lastname: Buevich
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Caldwell
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Mazzola
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Johannes
authors.initials: J
authors.lastname: Voigt
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Grzelak
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Reshma
authors.initials: R
authors.lastname: Kuvelkar
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Prescott T
authors.initials: PT
authors.lastname: Leach
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Terracina
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Michener
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Brad
authors.initials: B
authors.lastname: Smith
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Cox
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Grotz
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Leonard
authors.initials: L
authors.lastname: Favreau
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Mitra
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Irina
authors.initials: I
authors.lastname: Kazakevich
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: McKittrick
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: William
authors.initials: W
authors.lastname: Greenlee
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Kennedy
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jared N
authors.initials: JN
authors.lastname: Cumming
authors.affiliation: Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry*; D007097:Imines / Q000737:chemistry*; D008252:Macaca fascicularis; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007097:Imines; D053829:Amyloid Precursor Protein Secretases