Design of potent inhibitors of human β-secretase. Part 2

Freskos, John N.; Fobian, Yvette M.; Benson, Timothy E.; Moon, Joseph B.; Bienkowski, Michael J.; Brown, David; Emmons, Thomas L.; Heintz, R.; Laborde, A. L.; McDonald, Joseph J.; Mischke, Brent V.; Molyneaux, John M.; Mullins, Patrick B.; Prince, D. Bryan; Paddock, Donna J.; Tomasselli, Alfredo G.; Winterrowd, Greg

doi:10.1016/j.bmcl.2006.09.091

Cited by 31 publications

(20 citation statements)

References 3 publications

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“…Inhibitor 28 shows moderate BACE1 inhibitory activities, however, 29 and 30 show improved inhibitory activities and cell-based inhibition. The research group at Elan Pharmaceuticals and Pharmacia & Upjohn revealed a different type of BACE1 inhibitors (e.g., 31 and 32, IC 50 = 2 and 4 nM, respectively, Figure 4A) [64,65]. These compounds also show potent inhibitory activities in cultured cells.…”

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

confidence: 96%

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: 96%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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“…4). Pfizer reported on a hydroxyethyl amine-based inhibitor, 10, where the isophthalamide was replaced with an acyclic sulfone that could still access the S 2 and S 3 binding subsites [Freskos et al, 2007]. Compound 10 had an IC 50 value of 2 nM and an IC 50 value of 1 nM in the HEK cell assay, potency comparable to the previously described isophthalamide inhibitor series.…”

Section: Non-isophthalamide Hydroxyethylamine-based Inhibitorsmentioning

confidence: 87%

Progress toward the development of a viable BACE‐1 inhibitor

Stachel¹

2009

Drug Development Research

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Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive formation of insoluble amyloid plaque and fibrillary tangles. Plaques are extracellular constructs consisting primarily of Ab 42 derived from the catabolism of b-amyloid precursor protein (APP). b-Secretase (BACE-1) is the enzyme responsible for the initiatory cleavage event in APP catabolism. The central role of BACE-1 in the production of Ab 42 has made it an attractive target for drug development. However, the development of BACE-1 inhibitors has been hampered by difficulty in identifying inhibitors with acceptable pharmacokinetic and CNS penetration properties. The maturation of the BACE-1 drug discovery effort from typical peptidomimetic inhibitors to more novel structural classes is reviewed. Drug Dev

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“…Further optimization led to a highly potent inhibitor 26 with an IC 50 value of 2 nM and has shown excellent selectivity against cathepsin D (IC 50 = 474 nM). It has shown good cellular potency (IC 50 =1 nM) as well [42]. The X-ray crystal structure of inhibitor 26-bound BACE-1 shows the key interactions in the active site.…”

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

confidence: 99%

“…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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Design of potent inhibitors of human β-secretase. Part 2

Cited by 31 publications

References 3 publications

Advances in the identification of β-secretase inhibitors

Advances in the identification of β-secretase inhibitors

Progress toward the development of a viable BACE‐1 inhibitor

Memapsin 2 (Beta-Secretase) Inhibitors: Drug Development

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