Potent and selective isophthalamide S2 hydroxyethylamine inhibitors of BACE1

Kortum, Steven W.; Benson, Timothy E.; Bienkowski, Michael J.; Emmons, Thomas L.; Prince, D. Bryan; Paddock, Donna J.; Tomasselli, Alfredo G.; Moon, Joseph B.; Laborde, A. L.; Tenbrink, R. E.

doi:10.1016/j.bmcl.2007.03.096

Cited by 41 publications

(34 citation statements)

References 11 publications

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“…Researchers at Elan Pharmaceuticals reported a series of non-peptidic BACE1 inhibitors 28 --30 (IC 50 = 130, 20 and 5 nM, respectively, Figure 4A) with an isophthalic scaffold that is the same as the P 2 portion of compound 9 previously reported by the same research group [62,63]. These compounds have a hydroxyethylamine unit as a substrate transition-state analog instead of the statine unit in compound 9.…”

Section: Non-peptidic Bace1 Inhibitors By Structure-based Designmentioning

confidence: 94%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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Many BACE1 inhibitors have been designed using X-ray crystal structure-based drug design as well as through in silico screening. Nevertheless, there are serious problems with regards to deciding the best X-ray crystal structure for designing BACE1 inhibitors through computational approaches. There are two prominent configurations of BACE1 but there is still room for improvement. Future developments may make it possible to identify BACE1 inhibitors as potential drug candidates.

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Section: Non-peptidic Bace1 Inhibitors By Structure-based Designmentioning

confidence: 94%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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“…Early HEA-based inhibitors showed good inhibitory potency in biochemical and cell-based assays; however, they were not effective in vivo (Stachel et al, 2004;Freskos et al, 2007;Kortum et al, 2007;Maillard et al, 2007). Our data show that although potency is clearly important, within a series of 134 compounds with potency Ͻ100 nM (and most Ͻ30 nM), there was no correlation between in vivo PD efficacy and in vitro potency.…”

Section: Discussionmentioning

confidence: 71%

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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“…A series of hydroxyethylamine isostere and isophthalamide-derived inhibitors have been reported [41][42][43]. Inhibitor 25 (Fig.…”

Section: Development Of Other Drug-like Mema-psin 2 Inhibitorsmentioning

confidence: 99%

Memapsin 2 (Beta-Secretase) Inhibitors: Drug Development

Ghosh

Kumaragurubaran²,

Ling³

et al. 2008

CAR

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Memapsin 2 (beta-secretase, BACE 1) processing of beta-amyloid precursor protein is the first step in the pathway leading to the production of amyloid-beta, thus, it is a major target for the development of inhibitor drug for the treatment of Alzheimers's Disease. Although there are distinctive advantages of this protease as a drug target, the development of drug-like memapsin 2 inhibitors has been somewhat slow since the cloning of the protease seven years ago. Here we review the progress of memapsin 2 inhibitor development using crystal structure-based design cycles. Recent progress has evolved the inhibitors into sizes sufficiently small to penetrate cell membranes and the blood-brain barrier yet retain potency for the inhibition of Abeta production in cultured cells and experimental animals. Such progress lends optimism that clinically useful memapsin 2 inhibitors will eventually be developed.

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Potent and selective isophthalamide S2 hydroxyethylamine inhibitors of BACE1

Cited by 41 publications

References 11 publications

Advances in the identification of β-secretase inhibitors

Advances in the identification of 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

Memapsin 2 (Beta-Secretase) Inhibitors: Drug Development

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