Pharmacological Models for Preclinical Testing: From Mouse to Dog to Nonhuman Primates

Eriksen, Jason L.; Murphy, Michael P.; Head, Elizabeth

doi:10.1002/9780470594087.ch7

Cited by 1 publication

(3 citation statements)

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“…There is a high degree of sequence homology between the BACE1 and the APP sequences from mice (96.4%, 96.6%), rat (96.4%, 96.9%), dog (nd, 96.8%), and rhesus (99.6%, 99.5%) versus the human isoforms. − ,− The sequence differences in the BACE1 enzyme are not near the binding site (Figure ), and for APP, the closest residue that differs from the human sequence is at the P5′ site (Arg676Gly). There are no data to suggest that these sequence changes affect the processing of the APP by BACE1 enzyme across these species …”

Section: Introductionmentioning

confidence: 99%

“…To determine the efficacy of BACE1 inhibitors in vivo, rodent (mice and rat), dog, and primate (rhesus) models can be used to measure the lowering of the Aβ peptide levels in the brain and CSF. 38 Both the enzyme and substrate are well-Figure 1. Sequence alignment of full length BACE1 sequences from human, rhesus, dog, rat, and mouse.…”

Section: Introductionmentioning

confidence: 99%

“…There are no data to suggest that these sequence changes affect the processing of the APP by BACE1 enzyme across these species. 38 Several animal models are available and are used to test the long-term efficacy of BACE1 inhibitor compounds. These include transgenic mice expressing human APP with Swedish mutations that express higher levels of Aβ peptides relative to the wild-type, which facilitates the measurement of Aβ (Tg2576).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease

Yuan¹,

Shankar²,

Zheng³

et al. 2013

J. Med. Chem.

131

134

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The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-β (Aβ) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer's disease and dementia. The Aβ hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer's and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia. This review summarizes two distinct categories of inhibitors designed based on conformational states of "closed" and "open" forms of the enzyme. In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM). This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure-activity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data.

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