title: Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: conformational constraint to favor a bioactive conformation.
abstract: On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aβ(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States. mihirbaran.mandal@merck.com
authors.forename: Mihirbaran
authors.initials: M
authors.lastname: Mandal
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Zhu
authors.forename: Jared N
authors.initials: JN
authors.lastname: Cumming
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Liu
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.forename: Robert D
authors.initials: RD
authors.lastname: Mazzola
authors.forename: John P
authors.initials: JP
authors.lastname: Caldwell
authors.forename: Prescott
authors.initials: P
authors.lastname: Leach
authors.forename: Michael
authors.initials: M
authors.lastname: Grzelak
authors.forename: Lynn
authors.initials: L
authors.lastname: Hyde
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Terracina
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.forename: Reshma
authors.initials: R
authors.lastname: Kuvelkar
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Kennedy
authors.forename: Leonard
authors.initials: L
authors.lastname: Favreau
authors.forename: Kathleen
authors.initials: K
authors.lastname: Cox
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.forename: Alexei
authors.initials: A
authors.lastname: Buevich
authors.forename: Johannes
authors.initials: J
authors.lastname: Voigt
authors.forename: Hongwu
authors.initials: H
authors.lastname: Wang
authors.forename: Irina
authors.initials: I
authors.lastname: Kazakevich
authors.forename: Brian A
authors.initials: BA
authors.lastname: McKittrick
authors.forename: William
authors.initials: W
authors.lastname: Greenlee
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008252:Macaca fascicularis; D008958:Models, Molecular; D008968:Molecular Conformation; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D010539:Permeability; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011789:Quantum Theory; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C578492:3-(5-((7aR)-6-(5-fluoropyrimidin-2-yl)-2-imino-3-methyl-4-oxooctahydro-1H-pyrrolo(3,4-d)pyrimidin-7a-yl)thiophen-3-yl)benzonitrile; D016229:Amyloid beta-Peptides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009570:Nitriles; D010446:Peptide Fragments; D011743:Pyrimidines; D011744:Pyrimidinones; D013876:Thiophenes; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human