Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and β-secretase

Zhu, Young; Xiao, Kun; Ma, Li; Xiong, Bin; Fu, Yan; Yu, Haiping; Wang, Wei; Wang, Xin; Hu, Dawei; Peng, Hongli; Li, Jingya; Gong, Qi; Chai, Qian; Tang, Xi-Can; Zhang, Haiyan; Li, Jia; Shen, Jingkang

doi:10.1016/j.bmc.2008.12.067

Cited by 92 publications

(48 citation statements)

References 75 publications

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“…Overall, BACE1 has represented an attractive target for medicinal chemists across the pharmaceutical industry for more than a decade (Stachel, 2009), but progress has been slow. Despite impressive intrinsic potency, the compounds reported to date have struggled to produce in vivo, CNS pharmacodynamic (PD) effects under standard treatment protocols (Rajendran et al, 2008;Sankaranarayanan et al, 2009;Zhu et al, 2009;Malamas et al, 2010). Common limitations have included loss of potency in cellular systems, low oral bioavailability/high metabolic clearance, and inadequate access to the target compartment within the CNS, often driven by P-glycoprotein or other transport systems.…”

Section: Introductionmentioning

confidence: 99%

Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor

May¹,

Dean²,

Lowe³

et al. 2011

J. Neurosci.

349

384

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Section: Introductionmentioning

confidence: 99%

Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor

May¹,

Dean²,

Lowe³

et al. 2011

J. Neurosci.

349

384

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“…Great progress has been made in the last few years to design potent BACE1 inhibitors that can reduce brain Ab after oral administration. There are numerous reports studying the effects of BACE1 inhibition on cerebral spinal fluid (CSF) and/or brain Ab and other biomarkers in mice, rats, dogs, monkeys, and humans (Hussain et al, 2007;Elvang et al, 2009;Sankaranarayanan et al, 2009;Zhu et al, 2009;Fukumoto et al, 2010;May et al, 2011;Dineen et al, 2012;Weiss et al, 2012). Sankaranarayanan et al (2009) were the first to show in vivo reduction of plasma and CSF Ab after single or multiple oral administration of a BACE1 inhibitor, N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4-oxadiazol-2-yl}-3-chloro-6-((2-methoxyethyl){[(1S,2S)-2-methylcyclopropyl]methyl}amino)pyridin-2-yl]-Nmethylmethanesulfonamide, in nonhuman primates (rhesus monkeys).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys: Development of a Predictive Model for Amyloid Precursor Protein Processing

et al. 2013

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This study was conducted to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of two novel inhibitors of b-site amyloid precursor protein (APP)-cleaving enzyme (BACE1), 4a9S,10a9S)-2-amino-89-(2-fluoropyridin-3-yl)- 1-methyl-39,49,4a9,10a9-tetrahydro-19H-spiro[imidazole-4,109-pyrano[4,3-b] , and to develop a PK-PD model to predict in vivo effects based solely on in vitro activity and PK. GNE-629 and GNE-892 concentrations and PD biomarkers including amyloid b (Ab) in the plasma and cerebrospinal fluid (CSF), and secreted APPb (sAPPb) and secreted APPa (sAPPa) in the CSF were measured after a single oral administration of GNE-629 (100 mg/kg) or GNE-892 (30 or 100 mg/kg) in cynomolgus monkeys. A mechanistic PK-PD model was developed to simultaneously characterize the plasma Ab and CSF Ab, sAPPa, and sAPPb using GNE-629 in vivo data. This model was used to predict the in vivo effects of GNE-892 after adjustments based on differences in in vitro cellular activity and PK. The PK-PD model estimated GNE-629 CSF and free plasma IC 50 of 0.0033 mM and 0.065 mM, respectively. These differences in CSF and free plasma IC 50 suggest that different mechanisms are involved in Ab formation in these two compartments. The predicted in vivo effects for GNE-892 using the PK-PD model were consistent with the observed data. In conclusion, a PK-PD model was developed to mechanistically describe the effects of BACE1 inhibition on Ab, sAPPb, and sAPPa in the CSF, and Ab in the plasma. This model can be used to prospectively predict in vivo effects of new BACE1 inhibitors using just their in vitro activity and PK data.

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“…[11] Dual AChE and MAO inhibitors Coumarin derivatives, [12] 1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazoline derivatives, [13] xanthones [14] Dual AChE and serotonin transporter inhibitors (S)-2j (RS-1259) [15] Dual binding site AChE inhibitors AP2238, [16] tacrine-thiadiazolidinone hybrids [17] Dual AChE and Abeta aggregation inhibitors Propidium-tacrine heterodimer, [18] tacripyrines (tacrine-dihydropyridine hybrids obtained by combining tacrine with nimodipine), [19] Congo red dye, [20] huperzine A (HupA)-based bivalent ligands [21] Dual AChE and NMDA inhibitors Bis (7)-tacrine, i.e. (1,7-N-heptylene-bis-9,9′-amino-1,2,3,4-tetrahydroacridine) [22] Dual AChE and b-secretase (BACE) inhibitors [23] Dual acetylcholinesterase inhibitors and antioxidants PMS777 [24] Psychosis Dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors…”

Section: Dual Cholinesterase Inhibitorsmentioning

confidence: 99%

“…Furthermore, intracerebroventricular injection of this compound in APP-transgenic mice caused a 29% reduction of b-amyloid production, thereby indicating that it is a good lead compound for further evaluation. [23] …”

Section: Dual Ache and N-methyl-d-aspartate Inhibitorsmentioning

confidence: 99%

Dual inhibition: a novel promising pharmacological approach for different disease conditions

Patyar

Prakash

Medhi

2011

Journal of Pharmacy and Pharmacology

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To overcome the problems associated with polypharmacy, which include medication non compliance, adverse drug reactions, drug-drug interactions and increased pill-burden, various strategies, such as sustained-release drugs and fixed-dose combination regimens (polypills), have been developed. Out of these, a novel and very much promising approach is the use of dual-action drugs. Amongst the dual-action drugs, there is a class of compounds known as dual inhibitors, which possess the dual inhibitory activity. The most common examples of dual inhibitors are rivastigmine, ladostigil, asenapine, phenserine, amitriptyline, clomipramine, doxepin and desipramine. This review article focuses on the conventional drugs used in different diseases which possess dual inhibition activity as well as those which are still in the preclinical/clinical phase.

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Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and β-secretase

Cited by 92 publications

References 75 publications

Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor

Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor

Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys: Development of a Predictive Model for Amyloid Precursor Protein Processing

Dual inhibition: a novel promising pharmacological approach for different disease conditions

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