CX717 is an
ampakine
Ampakines, also stylized as AMPAkines, are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA recepto ...
compound created by Christopher Marrs and Gary Rogers in 1996 at
Cortex Pharmaceuticals
RespireRx Pharmaceuticals Inc. (formerly Cortex Pharmaceuticals, Inc.) () is a pharmaceutical company based in Glen Rock, New Jersey specializing in positive allosteric modulators of the AMPA receptor known as Ampakines.
History
In February 2005, ...
. It affects the neurotransmitter
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, with trials showing the drug improves cognitive functioning and memory.
Approval process
In 2005 the
U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
(FDA) accepted Cortex Pharmaceuticals'
Investigational New Drug (IND) application to initiate pilot Phase II clinical trials in the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
.
Also, in 2005, the
United States Department of Defense
The United States Department of Defense (DoD, USDOD or DOD) is an executive branch department of the federal government charged with coordinating and supervising all agencies and functions of the government directly related to national secu ...
funded a study to look into CX717 and the physiological effects of sleepiness. The study found that
rhesus monkey
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...
s performed faster and better after receiving the drug, and it counteracted the effects of sleep deprivation.
However, a 2006 study funded by
DARPA
The Defense Advanced Research Projects Agency (DARPA) is a research and development agency of the United States Department of Defense responsible for the development of emerging technologies for use by the military.
Originally known as the Adv ...
found that CX717 did not improve cognitive performance in humans subjected to simulated night shift work.
In early March 2006 Cortex reported that, in a small pilot Phase II study, CX717 had demonstrated positive clinical and statistical results on the primary endpoint, the
ADHD
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
rating scale and the sub-scales related to attention and hyperactivity which are used for the approval of all currently available ADHD treatments. According to a Cortex Pharmaceuticals press release, "Consistent with all previous studies involving over 220 patients and healthy adults, this study demonstrated that CX717 was safe, well tolerated, and produced no increase in heart rate, blood pressure or other cardiovascular side effects".
In April 2007 Cortex Pharmaceuticals submitted two large data packages to the FDA regarding CX717. One data set went to the FDA's Division of Neurology Drug Products for the treatment of
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, while the other went to the Division of Psychiatry Products where the company filed a second CX717 IND for the treatment of ADHD. According to a Cortex Pharmaceuticals press release, the submitted data package "provides clear evidence that the specific histopathological changes seen in animal toxicology studies, which previously caused the FDA to put CX717 on clinical hold, is a postmortem fixation artifact and is not found in the tissue of the animal when it is still living".
Roger G Stoll PhD, Chief Executive Officer of Cortex, stated,
“When CX717 was removed from clinical hold on October 6, 2006 by the Neurology Division a dose was permitted for continuing a study in patients with Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, but that dose was too low to permit the assessment of the drug in patients with ADHD. Further information was needed to better understand the cause of the histopathological changes. We now have a substantial data base which clearly documents the fact that the histological changes of concern occur postmortem when the fixative solution is used to prepare the slides of the tissue specimens.”
However, in October 2007 the FDA denied Cortex's IND application for a Phase IIb study of CX717 for treatment of ADHD, based on the same animal toxicology results. Cortex responded by inactivating the application, although it will "continue its plans to develop CX717 for the acute treatment of respiratory depression (RD) and continue its study of CX717 in its Alzheimer’s disease PET scan study. Cortex believes that the IND application previously filed with the Division of Neurology Products of the FDA for the treatment of Alzheimer’s disease will not be affected by the actions of the DPP." The company hopes that after the use of the compound in treating a high-risk acute condition is approved and well-established, the risks of longer-term use at higher doses, such as for treatment of ADHD, will be shown to be less than the FDA had concluded.
Use for reversal of respiratory depression
The relatively poor oral bioavailability and blood–brain barrier penetration of CX-717 ultimately led to Cortex abandoning development of the 800 mg oral formulation of CX-717 for ADHD, although research into its action in the brain continues.
However the unexpected discovery of the strong
respiratory stimulant
Doxapram hydrochloride (marketed as Dopram, Stimulex or Respiram) is a respiratory stimulant. Administered intravenously, doxapram stimulates an increase in tidal volume, and respiratory rate.
Mechanism of action
Doxapram stimulates chemorecep ...
effects of the ampakine drugs on the
pre-Botzinger complex of the brain has led to continued development of an intravenous formulation of CX-717 for use alongside
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
analgesics,
along with an oral formulation of CX-1739, which is around 3-5x more potent than CX-717 and has better oral bioavailability, and is being trialled for treatment of
sleep apnea
Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many times ...
. Further research has investigated the neurological mechanisms behind the anti-respiratory depressant effects of CX-717,
and demonstrated that it can be used in humans alongside opioid drugs to reduce this side effect without affecting analgesia.
Related AMPAkines
Other AMPAkine drugs from Cortex Pharmaceuticals such as
CX-546
CX-546 is an ampakine drug developed by Cortex Pharmaceuticals.
It has been proposed as a treatment for schizophrenia. CX-546 was the second drug of note to come out of the Cortex research program, after CX-516, but while it was an improvement o ...
and
CX-614
CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors.
Chronic CX-614 treatments produce rapid increases in the synthesis of the brain-derived neurotrophic factor BDNF which has ...
have already been researched for use in treating
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and ADHD. These drugs were reasonably effective at reducing the symptoms of Alzheimer's and it was hoped that they could also slow the progression of the disease, but both CX-546 and CX-614 have poor bioavailability, and are only active at very high doses of 1000 mg or more. CX-717 and CX-1739 are newer and more potent drugs in the same series.
See also
*
AMPA receptor positive allosteric modulator
AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system.
Medical ...
References
*
*
Cortex Pharmaceuticals press release
{{DEFAULTSORT:Cx717
Ampakines
Benzoxadiazoles
4-Morpholinyl compunds
Stimulants
AMPA receptor positive allosteric modulators
Experimental drugs
Enones