Novel target (ER stress) for AD

1. BY- ARGHYA CHOWDHURY (ROLL NO.: 18162027), M.PHARM(1ST YEAR)
Department of Pharmaceutical Engineering and Technology ,IITBHU, Varanasi
Novel target for the treatment of Alzheimer’s Disease

2. Introduction
 Alzheimer's disease first described by Alois Alzheimer in 1907.
 Alzheimer’s disease (AD) is a progressive neurodegenerative disease that leads
to a gradual loss of cognitive function and ultimately dementia.
 The only approved therapies are neurotransmitter modulators, consisting of
cholinesterase inhibitors and the NMDA receptor antagonist memantine.
 There is a clear need for therapies that can target causative mechanism of AD
progression.

3. The novel target-ER stress
The relation between ER stress and ER stress induced apoptosis

4. Findings
 Low ER Ca2+ coupled with rising cytosolic Ca2+ have been established as a
major cause of ER stress-induced apoptosis.
 Dysfunctional SERCA(sarco/endoplasmic reticulum Ca2+-ATPase) is also a
cause of ER stress.
 Increasing SERCA activity maintains ER calcium, and thus ER function.
 SERCA activation can sequester more cytosolic Ca2+ and prevent the apoptosis
induced by mitochondrial signaling.
 ER stress is a major cause of brain mass loss in AD.

5. Drug discovery
 CDN1163 is a quinoline derivative discovered via medicinal chemistry
optimization of a series of hits discovered via high throughput screening of a
20,000 member small molecule library.
 CDN1163 is potent and has been shown to be an allosteric activator that directly
binds SERCA.
 CDN1163 has been shown to increase SERCA in microsomes, enhance Ca2+
uptake into the ER, and increase SERCA activity in vivo.

6. Promising facts
 CDN1163 and derivatives show acceptable pharmacokinetic profiles in mouse.
 The compound shows sufficient blood levels when dosed orally, and has an overall
promising bioavailability.
 The compound also does not inhibit the major CYP enzymes when tested up to 5 µM.
 The concentrations of CDN1163 in mice brains show almost 3 times the plasma
concentration at 1 h after administration.

7. Supportive experiment
 The 4-month old APP/PSEN1 double-transgenic
mice were tested after the last administration of
CDN1163 or vehicle solution according to the
dosing schedule (daily, 5 days per week for 4
weeks).
 The mice were shown a visible platform that was
subsequently removed.
 The distance that the mice swam searching for the
platform was measured, with a shorter distance
indicating increased memory.
The Morris Water Maze Test (MWM)

8. Conclusion
There is an urgent need for disease-modifying therapeutics for AD that target the key
pathophysiological features linked to memory and cognitive loss. The above compound shows the
ability to rescue neurons in vitro and demonstrate efficacy in transgenic animal models of AD.
This includes significant improvement on many behavioral measures of memory and cognition.
Hopefully, this pathway could be lead to medicines that will benefit patients.

9. References
 K. Krajnak, R. Dahl Bioorganic & Medicinal Chemistry Letters 28 (2018) 1591–1594
 Apoptosis (2009) 14:1424–1434 DOI 10.1007/s10495-009-0400-4

10. Thanks for listening