# Neuroprotective Small Molecules as Novel Treatments for ALS

> **NIH VA I01** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2020 · —

## Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly fatal neurodegenerative disease involving
death of upper and lower motor neurons controlling voluntary muscle movement. Current prevalence of ALS in
the U.S. is estimated at 20,000, with about 5,000 new cases per year. Though people of all races and
ethnicities are equally susceptible to ALS, this disease strikes military veterans more frequently than the
general population. Men are also more frequently affected than women. Although ALS is multi-factorial in
origin, disease progression and severity uniformly advance as motor neurons die. It is thus expected that
neuroprotective agents that block motor neuron death might provide new therapeutic options for patients.
However, there are no drugs available that block neuronal cell death, in ALS or any other form of
neurodegeneration. Here, we seek to improve the potency, efficacy and safety of the P7C3-class of
neuroprotective molecules that we have developed, in hopes of addressing this unmet need. We have
previously shown that P7C3-A20, a highly active analog of P7C3, delays motor neuron cell death and loss of
motor function in G93A-SOD1 transgenic mice, a preclinical model of ALS. We now propose to evaluate the
efficacy of our most highly evolved analogue of P7C3, known as (-)-P7C3-S243, which has shown efficacy in
rigorous preclinical models of Parkinson’s disease and blast-mediated traumatic brain injury (TBI). Most
notably, axonal degeneration is a prominent feature of ALS, and (-)-P7C3-S243 specifically blocks injury-
induced axonal degeneration in the absence of neuron cell body death in this model of TBI. We have made
substantial progress in medicinal chemistry, and (-)-P7C3-S243 lacks the aniline moiety of the original P7C3
chemical and shows no overt toxicity, including no inhibition of the human hERG channel. Furthermore,
prolonged administration of (-)-P7C3-S243 is well tolerated in rodents at doses 10- to 30-fold higher than
required for therapeutic efficacy. Importantly, we have also recently identified the molecular target of the P7C3
molecules as nicotinamide phosphoribosyltransferase (NAMPT). NAMPT catalyzes the rate-limiting step in
nicotinamide adenine dinucleotide (NAD) salvage, and active analogues of P7C3 enhance its conversion of
nicotinamide into nicotinamide mononucleotide (NMN) and NAD in living cells. Strong historical evidence has
long predicted that drugs capable of enhancing NAD levels should be uniquely beneficial in treatment of
neurodegenerative disease. In addition to mechanistic insight, knowing the molecular target of P7C3 enables
us to explore wider swaths of chemistry than previously allowed. Efficacy of new molecules will first be
evaluated by in vitro assays of activity, and successful leads will then be evaluated for in vitro and in vivo
pharmacokinetic properties. Molecules passing these criteria will be subsequently evaluated in in vivo assays
of hippocampal neuroprotection, our original scree...

## Key facts

- **NIH application ID:** 10057083
- **Project number:** 7I01BX002444-06
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** ANDREW A PIEPER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 7
- **Project period:** 2015-01-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057083

## Citation

> US National Institutes of Health, RePORTER application 10057083, Neuroprotective Small Molecules as Novel Treatments for ALS (7I01BX002444-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10057083. Licensed CC0.

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