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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Oral
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid beta-Peptides / metabolism
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cerebral Cortex / metabolism
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Crystallography, X-Ray
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HEK293 Cells
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Humans
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Macaca fascicularis
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Models, Molecular
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Molecular Conformation
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Nitriles / chemical synthesis*
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Nitriles / pharmacokinetics
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Nitriles / pharmacology
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Peptide Fragments / metabolism
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Permeability
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / pharmacokinetics
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Pyrimidinones / pharmacology
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Quantum Theory
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Thermodynamics
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Thiophenes / chemical synthesis*
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Thiophenes / pharmacokinetics
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Thiophenes / pharmacology
Substances
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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
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Amyloid beta-Peptides
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Bridged Bicyclo Compounds, Heterocyclic
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Nitriles
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Peptide Fragments
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Pyrimidines
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Pyrimidinones
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Thiophenes
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amyloid beta-protein (1-40)
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human