View source for CX717

{{Short description|Ampakine}}
{{Infobox drug
| Verifiedfields = changed
| verifiedrevid =
| IUPAC_name               = 5-(Morpholine-4-carbonyl)-2,1,3-benzoxadiazole<ref>{{cite journal | vauthors = Radin DP, Purcell R, Lippa AS | title = Oncolytic Properties of Ampakines ''In Vitro'' | journal = Anticancer Research | volume = 38 | issue = 1 | pages = 265–269 | date = January 2018 | pmid = 29277782 | doi = 10.21873/anticanres.12217 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Purcell R, Lynch G, Gall C, Johnson S, Sheng Z, Stephen MR, Cook J, Garman RH, Jortner B, Bolon B, Radin D, Lippa A | display-authors = 6 | title = Brain Vacuolation Resulting From Administration of the Type II Ampakine CX717 Is An Artifact Related to Molecular Structure and Chemical Reaction With Tissue Fixative Agents | journal = Toxicological Sciences | volume = 162 | issue = 2 | pages = 383–395 | date = April 2018 | pmid = 29253237 | doi = 10.1093/toxsci/kfx277 | doi-access = free }}</ref>
| image                    = CX717.svg
<!--Identifiers-->
| CAS_number_Ref           = {{cascite|correct|CAS}}
| CAS_number               = 867276-98-0
| UNII_Ref                 = {{fdacite|correct|FDA}}
| UNII                     = 7I12YTA3QM
| ATC_prefix               = None
| ATC_suffix               =
| PubChem                  = 3323368
| ChemSpiderID             = 2570822
<!--Chemical data-->
| C=11 | H=11 | N=3 | O=3
| smiles = C1COCCN1C(=O)C2=CC3=NON=C3C=C2
| StdInChI = 1S/C11H11N3O3/c15-11(14-3-5-16-6-4-14)8-1-2-9-10(7-8)13-17-12-9/h1-2,7H,3-6H2
| StdInChIKey = KFRQROSRKSVROW-UHFFFAOYSA-N
| molecular_weight         =
| bioavailability          =
| metabolism               =
| elimination_half-life    =
| excretion                =
| pregnancy_category       =
| legal_status             =
| routes_of_administration = [[Oral administration|By mouth]], IV
}}
'''CX717''' is an [[ampakine]] compound created by Christopher Marrs and Gary Rogers in 1996<ref>{{cite patent | country = US | number = 6110935 |title=Benzofurazan compounds for enhancing glutamatergic synaptic responses | inventor = Rogers GA, Marrs CM | assign1 = University of California | gdate = 29 August 2000 | postscript = . }}</ref> at [[Cortex Pharmaceuticals]]. It affects the neurotransmitter [[glutamate]], with trials showing the drug improves cognitive functioning and memory.<ref name="pmid18985324">{{cite journal | vauthors = Hampson RE, España RA, Rogers GA, Porrino LJ, Deadwyler SA | title = Mechanisms underlying cognitive enhancement and reversal of cognitive deficits in nonhuman primates by the ampakine CX717 | journal = Psychopharmacology | volume = 202 | issue = 1–3 | pages = 355–369 | date = January 2009 | pmid = 18985324 | pmc = 3107999 | doi = 10.1007/s00213-008-1360-z }}</ref>
==Approval process==
In 2005 the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) accepted Cortex Pharmaceuticals' [[Investigational New Drug]] (IND) application to initiate pilot Phase II clinical trials in the [[United States]].
Also, in 2005, the [[United States Department of Defense]] funded a study to look into CX717 and the physiological effects of sleepiness. The study found that [[rhesus monkey]]s performed faster and better after receiving the drug, and it counteracted the effects of sleep deprivation.<ref name="pmid16104830">{{cite journal | vauthors = Porrino LJ, Daunais JB, Rogers GA, Hampson RE, Deadwyler SA | title = Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates | journal = PLOS Biology | volume = 3 | issue = 9 | pages = e299 | date = September 2005 | pmid = 16104830 | pmc = 1188239 | doi = 10.1371/journal.pbio.0030299 | doi-access = free }}</ref><ref name="pmid18985324"/>
However, a 2006 study funded by [[DARPA]] found that CX717 did not improve cognitive performance in humans subjected to simulated night shift work.<ref>{{cite web |url=http://www.cortexpharm.com/html/news/06/06-21-06.html |title= Top-line findings on CX717 from the DARPA-sponsored shift work simulation study will be presented at sleep 2006 meeting | work = Cortex News & Events |access-date=2007-10-21 |archive-url = https://web.archive.org/web/20070927230732/http://www.cortexpharm.com/html/news/06/06-21-06.html <!-- Bot retrieved archive --> |archive-date = 2007-09-27}}</ref>
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]] 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]], 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".<ref>{{cite web|url=http://www.cortexpharm.com/news/07/txt_041807.html|title=Cortex's AMPAKINE CX-717 Toxicology Data Package Submitted to FDA|access-date=2009-03-31|archive-url=https://web.archive.org/web/20090106143500/http://www.cortexpharm.com/news/07/txt_041807.html|archive-date=2009-01-06|url-status=dead}}</ref>
Roger G Stoll PhD, chief executive officer of Cortex, stated, <blockquote>
"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]], 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."
</blockquote>
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."<ref>{{cite web |url=http://www.businesswire.com/portal/site/home/permalink/?ndmViewId=news_view&newsId=20071011005369&newsLang=en |title= FDA's Psychiatric Division has Rejected Cortex's Request to Study CX717 in Phase IIb ADHD Study |access-date=2008-02-28 }}</ref> 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&nbsp;mg oral formulation of CX-717 for ADHD,<ref>{{Cite web |url=http://www.cortexpharm.com/clinicaldev/txt_clinicdev.html |title=Untitled Document |access-date=2009-07-20 |archive-url=https://web.archive.org/web/20090406235402/http://www.cortexpharm.com/clinicaldev/txt_clinicdev.html |archive-date=2009-04-06 |url-status=dead }}</ref> although research into its action in the brain continues.<ref name="pmid18985324"/> However the unexpected discovery of the strong [[respiratory stimulant]] 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]] analgesics,<ref name="pmid19461299">{{cite journal | vauthors = Ren J, Ding X, Funk GD, Greer JJ | title = Ampakine CX717 protects against fentanyl-induced respiratory depression and lethal apnea in rats | journal = Anesthesiology | volume = 110 | issue = 6 | pages = 1364–1370 | date = June 2009 | pmid = 19461299 | doi = 10.1097/ALN.0b013e31819faa2a | doi-access = free }}</ref> along with an oral formulation of CX-1739, which is around 3-5× more potent than CX-717 and has better oral bioavailability, and is being trialled for treatment of [[sleep apnea]].<ref>{{Cite web |url=http://www.cortexpharm.com/news/news09.html |title=Cortex Annual Shareholder Meeting Notification | work = Cortex Pharmaceuticals Press | date = 1 June 2009 |access-date=20 July 2009 |archive-url=https://web.archive.org/web/20090223104403/http://www.cortexpharm.com/news/news09.html|archive-date=23 February 2009 |url-status=dead }}</ref> Further research has investigated the neurological mechanisms behind the anti-respiratory depressant effects of CX-717,<ref name="pmid20098731">{{cite journal | vauthors = Lorier AR, Funk GD, Greer JJ | title = Opiate-induced suppression of rat hypoglossal motoneuron activity and its reversal by ampakine therapy | journal = PLOS ONE | volume = 5 | issue = 1 | pages = e8766 | date = January 2010 | pmid = 20098731 | pmc = 2808240 | doi = 10.1371/journal.pone.0008766 | veditors = Hochman S | doi-access = free | bibcode = 2010PLoSO...5.8766L }}</ref> and demonstrated that it can be used in humans alongside opioid drugs to reduce this side effect without affecting analgesia.<ref name="pmid19907420">{{cite journal | vauthors = Oertel BG, Felden L, Tran PV, Bradshaw MH, Angst MS, Schmidt H, Johnson S, Greer JJ, Geisslinger G, Varney MA, Lötsch J | display-authors = 6 | title = Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia | journal = Clinical Pharmacology and Therapeutics | volume = 87 | issue = 2 | pages = 204–211 | date = February 2010 | pmid = 19907420 | doi = 10.1038/clpt.2009.194 | s2cid = 10723185 }}</ref>
==Related AMPAkines==
Other AMPAkine drugs from Cortex Pharmaceuticals such as [[CX-546]] and [[CX-614]] have already been researched for use in treating [[Alzheimer's disease]] 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&nbsp;mg or more. CX-717 and CX-1739 are newer and more potent drugs in the same series.<ref>{{cite journal | vauthors = Mueller R, Li YX, Hampson A, Zhong S, Harris C, Marrs C, Rachwal S, Ulas J, Nielsson L, Rogers G | display-authors = 6 | title = Benzoxazinones as potent positive allosteric AMPA receptor modulators: part I | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 13 | pages = 3923–3926 | date = July 2011 | pmid = 21636275 | doi = 10.1016/j.bmcl.2011.05.026 }}</ref><ref>{{cite journal | vauthors = Mueller R, Rachwal S, Tedder ME, Li YX, Zhong S, Hampson A, Ulas J, Varney M, Nielsson L, Rogers G | display-authors = 6 | title = Substituted benzoxazinones as potent positive allosteric AMPA receptor modulators: part II | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 13 | pages = 3927–3930 | date = July 2011 | pmid = 21636273 | doi = 10.1016/j.bmcl.2011.05.024 }}</ref><ref>{{cite journal | vauthors = Mueller R, Rachwal S, Lee S, Zhong S, Li YX, Haroldsen P, Herbst T, Tanimura S, Varney M, Johnson S, Rogers G, Street LJ | display-authors = 6 | title = Benzotriazinone and benzopyrimidinone derivatives as potent positive allosteric AMPA receptor modulators | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 20 | pages = 6170–6175 | date = October 2011 | pmid = 21889339 | doi = 10.1016/j.bmcl.2011.07.098 }}</ref>
== See also ==
* [[AMPA receptor positive allosteric modulator]]
== References ==
{{Reflist|2}}
== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Bast T, da Silva BM, Morris RG | title = Distinct contributions of hippocampal NMDA and AMPA receptors to encoding and retrieval of one-trial place memory | journal = The Journal of Neuroscience | volume = 25 | issue = 25 | pages = 5845–5856 | date = June 2005 | pmid = 15976073 | pmc = 6724786 | doi = 10.1523/JNEUROSCI.0698-05.2005 }}
* {{cite journal | vauthors = Arai AC, Kessler M, Rogers G, Lynch G | title = Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466 | journal = Molecular Pharmacology | volume = 58 | issue = 4 | pages = 802–813 | date = October 2000 | pmid = 10999951 | doi = 10.1124/mol.58.4.802 | url = http://nootropics.com/ampakines/cx614.html | url-status = dead | s2cid = 6489143 | archive-url = https://web.archive.org/web/20050307192645/http://www.nootropics.com/ampakines/cx614.html | archive-date = 2005-03-07 }}
* {{cite web | title = Cortex's AMPAKINE CX717 Toxicology Data Package Submitted To FDA | url = http://www.cortexpharm.com/html/news/07/04-18-07.html | work =Cortex Pharmaceuticals press release | date = 18 April 2007 | archive-url = https://web.archive.org/web/20070927230738/http://www.cortexpharm.com/html/news/07/04-18-07.html | archive-date = 2007-09-27 }}
{{refend}}
{{Ionotropic glutamate receptor modulators}}
{{DEFAULTSORT:Cx717}}
[[Category:Ampakines]]
[[Category:Benzoxadiazoles]]
[[Category:4-Morpholinyl compounds]]
[[Category:Stimulants]]
[[Category:AMPA receptor positive allosteric modulators]]
[[Category:Experimental drugs]]
[[Category:Enones]]