Design and synthesis of aminohydantoins as potent and selective human β-secretase (BACE1) inhibitors with enhanced brain permeability
Graphical abstract
Small R3 groups decrease P-gP affinity, TPSA, and molecular weight, which result in enhancement of the brain permeability of the compound.
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Design, synthesis and evaluation of 2-amino-imidazol-4-one derivatives as potent β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors
2019, Bioorganic and Medicinal Chemistry LettersIdentification of new BACE1 inhibitors using Pharmacophore and Molecular dynamics simulations approach
2017, Journal of Molecular Graphics and ModellingCitation Excerpt :Based on experimental IC50 values, 14 structures were retrieved as BACE1 complexes from PDB. The PDB-IDs are 2QMG [29], 2XFK [30], 3LPK [31], 2VNM [32], 3K5G [33], 2VKM [34], 3R2F [35], 4B00 [22], 4D8C [36], 4DI2 [37], 3LHG [38], 3OOZ [39], 3IXJ [40], 3IXK [41] along with IC50 value has been tabulated in (Table SP2). This cocrystal inhibitor bound BACE 1 structures were subjected to superimposition in order to analyze the binding mode in terms of prioritizing the subsites of catalytic pocket.
Design and synthesis of 5-cyclopropyl substituted cyclic acylguanidine compounds as BACE1 inhibitors
2016, Chinese Chemical LettersCitation Excerpt :To date, different structural classes BACE1 inhibitors have been designed and developed [7], but it is still a challenge to discover brain penetration BACE1 inhibitor with low molecule weight, potent activity and high selectivity. A cyclic acylguanidine compound, compound 1, which was discovered each other independently by Schering-Plough [8], Wyeth [9] and Pfizer [10], is a weak BACE1 inhibitor (IC50 = 7.1 μmol/L) [8] with brain penetration. This finding is a milestone to the development of BACE1 inhibitor based on the amyloid cascade hypothesis.
Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE)
2015, Bioorganic and Medicinal Chemistry LettersDifferential roles of Aβ processing in hypoxia-induced axonal damage
2015, Neurobiology of DiseaseCitation Excerpt :A role for Aβ in hypoxia-induced compromise of axonal structure was suggested by reports that hypoxia-induced alterations of APP processing result in increased levels of Aβ accumulation (Li et al., 2009), and we have confirmed that endogenous Aβ-40 and Aβ-42 levels are elevated in retinal explants exposed to hypoxic versus normoxic conditions (Supplementary Fig. 4). Therefore, we asked whether production of an APP product is necessary for early-stage hypoxia-induced compromise of retinal axonal structure by using pharmacological inhibitors preventing BACE1 (BI131) and γ-secretase (GSI642) cleavage of APP (Cole et al., 2009; Malamas et al., 2010). Treatment with BI131 and GSI642 reduced production of Aβ by over 90% (Fig. 3) and protected significantly against structural compromise in hypoxia-stressed retinal explants (Fig. 4A, B), consistent with a requirement for endogenous Aβ in hypoxia-induced impairment of axonal structure.
Iminopyrimidinones: A novel pharmacophore for the development of orally active renin inhibitors
2015, Bioorganic and Medicinal Chemistry Letters
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Present address: Lundbeck Research, USA.
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Present address: Vitae Pharmaceuticals, USA.
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Present address: Proteostasis Therapeutics, USA.
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Present address: AstraZeneca, USA.