Indiplon
{{Short description|Hypnotic sedative drug}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 461936069
| IUPAC_name = N-methyl-N-[3-[3-(thiophene-2-carbonyl)
pyrazolo[5,1-b]pyrimidin-7-yl]phenyl]acetamide
| image = Indiplon.svg
| width = 120
| tradename =
| pregnancy_US =
| legal_US =
| routes_of_administration = Oral
| bioavailability =
| metabolism =
| elimination_half-life = 1.5–1.8 hours
| excretion =
| IUPHAR_ligand = 4221
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 325715-02-4
| ATC_prefix = none
| ATC_suffix =
| PubChem = 6450813
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4953363
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 8BT63DA42E
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02640
| ChEBI = 188583
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 262075
| C = 20
| H = 16
| N = 4
| O = 2
| S = 1
| smiles = O=C(C1=CC=CS1)C2=C3N=CC=C(C4=CC(N(C)C(C)=O)=CC=C4)N3N=C2
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H16N4O2S/c1-13(25)23(2)15-6-3-5-14(11-15)17-8-9-21-20-16(12-22-24(17)20)19(26)18-7-4-10-27-18/h3-12H,1-2H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = CBIAWPMZSFFRGN-UHFFFAOYSA-N
}}
Indiplon (INN and USAN) is a unmarketed nonbenzodiazepine, hypnotic sedative that was developed in two formulations—an immediate-release formulation for sleep onset, and a modified-release (also called controlled-release or extended-release) version for sleep maintenance.
Pharmacology
= Pharmacodynamics =
Indiplon works by enhancing the action of the inhibitory neurotransmitter GABA, like most other nonbenzodiazepine sedatives. It primarily binds to the α1 subunits of the GABAA receptors in the brain.{{cite journal | vauthors = Petroski RE, Pomeroy JE, Das R, Bowman H, Yang W, Chen AP, Foster AC | title = Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 317 | issue = 1 | pages = 369–77 | date = April 2006 | pmid = 16399882 | doi = 10.1124/jpet.105.096701 | s2cid = 46510829 | url = http://jpet.aspetjournals.org/cgi/content/full/317/1/369 | format = PDF }}
= Pharmacokinetics =
Indiplon has a short elimination half-life of 1.5 to 1.8 hours in young and elderly subjects, respectively.{{cite journal | vauthors = Lemon MD, Strain JD, Hegg AM, Farver DK | title = Indiplon in the management of insomnia | journal = Drug Design, Development and Therapy | volume = 3 | pages = 131–142 | date = September 2009 | pmid = 19920929 | pmc = 2769245 | doi = 10.2147/dddt.s3207 | doi-access = free }}
Chemistry
Indiplon is a pyrazolopyramidine related to the nonbenzodiazepine hypnotic zaleplon.{{cite journal | vauthors = Sullivan SK, Petroski RE, Verge G, Gross RS, Foster AC, Grigoriadis DE | title = Characterization of the interaction of indiplon, a novel pyrazolopyrimidine sedative-hypnotic, with the GABAA receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 311 | issue = 2 | pages = 537–546 | date = November 2004 | pmid = 15256540 | doi = 10.1124/jpet.104.071282 }}
History
Indiplon was discovered at Lederle Laboratories (which was later acquired by Wyeth) in the 1980s and was called CL 285,489.{{cite book | vauthors = Neubauer DN | chapter = Indiplon | pages = 453–464 | title = GABA and Sleep: Molecular, Functional and Clinical Aspects. | veditors = Monti JS, Pandi-Perumal SR, Möhler H | publisher = Springer Science & Business Media | date = 2010 | isbn = 9783034602266 }}{{rp|454}} In 1998 Lederle licensed it, along with other early stage drug candidates, to DOV Pharmaceutical, a startup formed by former Lederle employees, and Dov exclusively sublicensed its rights in the drug to Neurocrine Biosciences in that same year. In 2002, Neurocrine entered into an agreement with Pfizer to develop the drug.
Indiplon was originally scheduled for release in 2007, when Sanofi-Aventis' popular hypnotic zolpidem lost its patent rights in the United States and thus became available as a much less expensive generic. In 2002, Neurocrine Biosciences had entered into an agreement with Pfizer to co-market indiplon in the US, in a deal worth a potential $400mn.{{cite web | url = http://www.fool.com/investing/general/2010/06/18/san-diegos-neurocrine-biosciences-scores-second-bi.aspx | title = San Diego's Neurocrine Biosciences Scores Second Big Deal in Two Days | work = The Motley Fool | date = 18 June 2010 }} However, following the issuing of a non-approvable letter for the modified-release 15 mg formulation and an approvable letter with stipulations for the 5 mg and 10 mg immediate-release version by the FDA in May 2006,{{cite web | url = http://www.thestreet.com/story/10285854/2/neurocrines-fda-nightmare.html | title = Neurocrine's FDA Nightmare | work = TheStreet.com | date = 16 May 2006 }} Pfizer ended its relationship with Neurocrine.{{cite web | url = http://www.thestreet.com/story/10293335/pfizer-drops-neurocrine-deal.html | title = Pfizer Drops Neurocrine Deal | work = TheStreet.com | date = 22 June 2006 }} Neurocrine's stock price dropped 60% on the news.{{cite web | url = https://money.cnn.com/2006/05/16/news/companies/indiplon/index.htm | title = Neurocrine stock price plunges 60 percent:FDA's mixed review of sleeping pill Indiplon could threaten Pfizer-Neurocrine partnership | work = CNN Money | date = 15 May 2006 }}
Following a resubmission, the FDA in December 2007 deemed Neurocrine's new drug application (NDA) 'approvable' in the 5 and 10 mg formulations,{{cite press release
| title = Neurocrine Receives Approvable Letter for Indiplon Capsules with Additional Safety and Efficacy Data Required by FDA
| publisher = Neurocrine Biosciences, Inc.
| date = 2007-12-13
| url = https://www.drugs.com/nda/indiplon_071213.html
| access-date = 2007-12-13
}} but requested new studies as a prerequisite to approval, including a clinical trial in the elderly, a safety study comparing adverse effects to those of similarly marketed drugs, and a preclinical study examining indiplon's safety in the third trimester of pregnancy.{{Cite web |title=Additional Pipeline Projects |url=http://www.neurocrine.com/index.cfm?navId=25 |publisher=Neurocrine |date=2012-02-16 |archive-url=https://web.archive.org/web/20120327204702/http://www.neurocrine.com/index.cfm?navId=25 |archive-date=2012-03-27 |url-status=live |access-date=2014-06-24 }}
Following the 2007 FDA letter, Neurocrine decided to discontinue all clinical and marketing development of Indiplon in the United States.
References
{{reflist}}
External links
- [https://www.drugs.com/NDA/indiplon_041019.html 2004 press release announcing Neurocrine's new product, Indiplon]
- [http://www.genome.jp/dbget-bin/www_bget?dr+D02640 GenomeNet Entry: D02640]
{{Hypnotics and sedatives}}
{{GABAAR PAMs}}