Design and Synthesis of Potent, Orally Efficacious Hydroxyethylamine Derived β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

Dineen, Thomas A.; Weiss, Matthew M.; Williamson, Toni; Acton, Paul D.; Babu‐Khan, Safura; Bartberger, Michael D.; Brown, James; Chen, Kui; Cheng, Yuan; Citron, Martin; Croghan, Michael D.; Dunn, Robert T.; Esmay, Joel; Graceffa, Russell F.; Harried, Scott S.; Hickman, Dean; Hitchcock, Stephen A.; Horne, Daniel B.; Huang, Hongbing; Imbeah-Ampiah, Ronke; Judd, Ted; Kaller, Matthew R.; Kreiman, Charles R.; La, Daniel S.; Li, Vivian; Lopez, Patrícia Luciana da Costa; Louie, Steven W.; Monenschein, Holger; Nguyen, Thomas; Pennington, Lewis D.; Miguel, Tisha San; Sickmier, E. Allen; Vargas, Hugo M.; Wahl, R.; Wen, Paul; Whittington, Douglas A.; Wood, Stephen; Xue, Qiufen; Yang, Bin; Patel, Vinod F.; Zhong, Wenge

doi:10.1021/jm300118s

Cited by 41 publications

(19 citation statements)

References 54 publications

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“…This apparent brain/CSF shift has been observed by others with both BACE1 and ␥-secretase inhibitors (Sankaranarayanan et al, 2009;Hawkins et al, 2011;Lu et al, 2011;Dineen et al, 2012;Weiss et al, 2012). There are several possible explanations for this observation.…”

Section: Discussionsupporting

confidence: 70%

Establishing the Relationship between In Vitro Potency, Pharmacokinetic, and Pharmacodynamic Parameters in a Series of Orally Available, Hydroxyethylamine-Derived β-Secretase Inhibitors

Wood

Wen

Zhang

et al. 2012

J Pharmacol Exp Ther

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Sequential proteolytic cleavage of the amyloid precursor protein (APP) by ␤-site APP-cleaving enzyme 1 (BACE1) and the ␥-secretase complex produces the amyloid-␤ peptide (A␤), which is believed to play a critical role in the pathology of Alzheimer's disease (AD). The aspartyl protease BACE1 catalyzes the rate-limiting step in the production of A␤, and as such it is considered to be an important target for drug development in AD. The development of a BACE1 inhibitor therapeutic has proven to be difficult. The active site of BACE1 is relatively large. Consequently, to achieve sufficient potency, many BACE1 inhibitors have required unfavorable physicochemical properties such as high molecular weight and polar surface area that are detrimental to efficient passage across the bloodbrain barrier. Using a rational drug design approach we have designed and developed a new series of hydroxyethylaminebased inhibitors of BACE1 capable of lowering A␤ levels in the brains of rats after oral administration. Herein we describe the in vitro and in vivo characterization of two of these molecules and the overall relationship of compound properties [e.g., in vitro permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and pharmacological potency] to the in vivo pharmacodynamic effect with more than 100 compounds across the chemical series. We demonstrate that high in vitro potency for BACE1 was not sufficient to provide central efficacy. A combination of potency, high permeability, low P-gp-mediated efflux, and low clearance was required for compounds to produce robust central A␤ reduction after oral dosing.

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Section: Discussionsupporting

confidence: 70%

Establishing the Relationship between In Vitro Potency, Pharmacokinetic, and Pharmacodynamic Parameters in a Series of Orally Available, Hydroxyethylamine-Derived β-Secretase Inhibitors

Wood

Wen

Zhang

et al. 2012

J Pharmacol Exp Ther

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“…Compound 64 was designed utilizing a 3-(2-thioazolyl)phenyl ligand at the P1 position. 197 Compound 64 exhibited a 59% reduction in brain Aβ levels after a 30 mg/kg oral dose in rats. Compound 65 with a terminal propene moiety as the P1 side chain showed an enzymatic IC 50 of 2 nM and a cellular IC 50 of 28 nM.…”

Section: Design Of Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 96%

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

2014

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BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's Disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's Disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

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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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Design and Synthesis of Potent, Orally Efficacious Hydroxyethylamine Derived β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

Cited by 41 publications

References 54 publications

Establishing the Relationship between In Vitro Potency, Pharmacokinetic, and Pharmacodynamic Parameters in a Series of Orally Available, Hydroxyethylamine-Derived β-Secretase Inhibitors

Establishing the Relationship between In Vitro Potency, Pharmacokinetic, and Pharmacodynamic Parameters in a Series of Orally Available, Hydroxyethylamine-Derived β-Secretase Inhibitors

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

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

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