Thiophene substituted acylguanidines as BACE1 inhibitors

Fobare, William F.; Solvibile, William R.; Robichaud, Albert J.; Malamas, Michael S.; Manas, Eric S.; Turner, James; Hu, Yun; Wagner, Erik; Chopra, Rajiv; Cowling, Rebecca; Jin, Guixian; Bard, Jonathan

doi:10.1016/j.bmcl.2007.08.010

Cited by 60 publications

(35 citation statements)

References 12 publications

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“…They identified two hit compounds, 51 and 55 (IC 50 = 3.7 and 38 µM, respectively), by performing HTS using a FRET assay. Nuclear magnetic resonance (NMR) showed that acylguanidine 51 was bound to BACE1, and isothermal titration calorimetry showed that this compound had a K d value of 2.8 µM [102][103][104][105][106][107][108]. The X-ray crystal structure showed that 51 was bound into the active site of BACE1 in the 'open form' state, and its guanidyl group interacted with two catalytic Asp residues of BACE1 by hydrogen bonds.…”

mentioning

confidence: 99%

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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confidence: 99%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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“…Novel acylguanidine-derived small molecule BACE-1 inhibitors have been identified by Harrison and co-workers [44,45]. These inhibitors interact with the two catalytic aspartic acids through four hydrogen bonding interactions and stabilize the protein in a flap-open conformation.…”

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

confidence: 98%

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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“…With the addition of the potency enhancing groups 16 displayed an IC 50 value of 110 nM, a 30-fold enhancement over the initial HTS lead. the Wyeth also reported on a series of thiophene-substituted acylguanidine inhibitors [Fobare et al, 2007] thiophene core was designed to replace the pyrrole in 15 to facilitate SAR analysis. Inhibitor 17 successfully accomplished this charge with a IC 50 value of 150 nM, similar in potency to the pyrrole-based inhibitor 16.…”

Section: Acylguanidines As Small Molecule Bace-1 Inhibitorsmentioning

confidence: 98%

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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Thiophene substituted acylguanidines as BACE1 inhibitors

Cited by 60 publications

References 12 publications

Advances in the identification of β-secretase inhibitors

Advances in the identification of β-secretase inhibitors

Memapsin 2 (Beta-Secretase) Inhibitors: Drug Development

Progress toward the development of a viable BACE‐1 inhibitor

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