AZD3293 [4-Methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''-amine]
is an oral, potent and selective small molecule inhibitor of BACE that has been
shown in Phase I studies to significantly and dose-dependently reduce levels of
amyloid beta (Aβ) in the cerebrospinal fluid (CSF) of Alzheimer’s patients and
healthy volunteers.
Amyloid
beta (Aβ) deposition in the brain is thought to be one of the causes of
Alzheimer's disease. It is expected that developing a new treatment for
Alzheimer's disease which reduces amyloid beta will not only improve symptoms,
but also help slow down the progression of the disease. AZD3293 may reduce the
overall amount of amyloid beta by inhibiting Beta-site amyloid precursor
protein cleaving enzyme (BACE). BACE1 is the first step in the processing of
APP to Aβ peptides, and its inhibition is an attractive target for therapeutic
intervention to stop the production of Aβ.
This
novel compound was discovered at AstraZeneca which have taken it up to Phase II
trials. In September 2014, AstraZeneca and Eli Lilly and Company (Lilly) announced an agreement to jointly develop and commercialise AZD3293 as a
potential treatment for Alzheimer’s disease.
Common Name: AZD3293
Synonyms: AZD3293; AZD 3293; AZD-3293; LY3314814; LY 3314814;
LY-3314814
IUPAC Name: 4-Methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''-amine
CAS Number: 1628076-74-3
Mechanism of Action: BACE1 Inhibitor; Beta-site
amyloid precursor protein (APP) cleaving enzyme 1 Inhibitor
Indication: Alzheimer's disease; Treatment of Dementia
Development Stage: Phase II
Company: AstraZeneca/Eli Lilly
The potency of AZD3293 in cellular models on
secretion of Aβ40 has been studied in SHSY5Y/APP cells (human neuronal cells
over expressing human APPwt), N2A cells (mouse neuronal cells), primary mouse
neurons and primary guinea pig neurons, using ELISA technology. Mice treated
with AZD3293 as a single administration, or repeated administrations twice
daily during 7 days, demonstrated a statistically significant dose- and time-dependent
reduction of the levels of Aβ40, Aβ42 and sAPPβ in plasma and brain. Guinea
pigs treated with AZD3293 as a single administration demonstrated a
statistically significant dose- and time-dependent reduction of the levels of Aβ40,
Aβ42 and sAPPβ in plasma, CSF and brain. In
vitro potency in mouse and guinea pig primary cortical neuronal cells was
strongly correlated to potency in mouse mouse and guinea pig in vivo potency [1].
To check the hypothesis that whether AZD3293
causes a dose dependent decrease of sAPPβ, and increase of sAPPα, clinical data
for soluble fragments alpha (sAPPα) and beta (sAPPβ) were collected during a
Multiple Ascending Dose study in elderly Healthy Volunteers, with the BACE
inhibitor AZD3293. It was expected that a dose dependent decrease of sAPPβ, and
increase of sAPPα would result from BACE1 inhibition in this study. CSF and
plasma in healthy volunteers were sampled pre-treatment and during 24h
continuous CSF sampling after 14 days of 15 and 50 mg dosing. Plasma and CSF
sAPP α and β data were compared to corresponding AZD3293 concentration data to
assess PK/PD correlations. The results were on the expected lines, where a
dose-dependent sustained decrease in CSF of sAPPβ, and broadly dose-dependent
increase of sAPPα, were observed. While sAPPα levels generally increased, data
were variable with no apparent dose dependency. Within the linear range of the
sAPPβ assay, a direct correlation between AZD3293 concentration (Cmax) and sAPPβ
inhibition was observed on a similar timeline to effects seen for Aβ40/42. The
observations are consistent with the hypothesized mechanism of action of
AZD3293 and indicate that sustained inhibition of BACE1 leads to reduced sAPPβ levels
and increased flux through the non-pathogenic α-secretase-mediated pathway [2].
References:
1. Haeberlein, S. B.; et. al.
AZD3293, a potent and selective orally active, brain-permeable BACE1 inhibitor.
Alzheimer's and Dementia 2013, 9(4), P813.
2. Hoglund, K.; et. al. Monitoring the soluble amyloid precursor protein alpha (sappa) and beta (sappb) fragments in plasma and csf from healthy individuals treated with bace inhibitor azd3293 in a multiple ascending dose study: pharmacokinetic and pharmacodynamic correlate. Alzheimer's and Dementia 2014, 10(4), P447.
2. Hoglund, K.; et. al. Monitoring the soluble amyloid precursor protein alpha (sappa) and beta (sappb) fragments in plasma and csf from healthy individuals treated with bace inhibitor azd3293 in a multiple ascending dose study: pharmacokinetic and pharmacodynamic correlate. Alzheimer's and Dementia 2014, 10(4), P447.
