Preladenant: Difference between revisions

{{Short description|Chemical compound}}

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| verifiedrevid = 415652771

| IUPAC_name = 2-(2-Furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7''H''-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine

| image = Preladenant.svg

| width = 250px

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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->

| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| legal_status = Investigational

| routes_of_administration = Oral

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<!--Identifiers-->

| IUPHAR_ligand = 5614

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 377727-87-2

| ATC_prefix = none

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| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

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| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = 950O97NUPO

| PubChem = 10117987

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 8293510

| KEGG = D09717

| synonyms = SCH-420814

<!--Chemical data-->

| C=25 | H=29 | N=9 | O=3

| smiles = COCCOc(cc4)ccc4N(CC3)CCN3CCn(c2nc1N)ncc2c(n5)n1nc5-c6occc6

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C25H29N9O3/c1-35-15-16-36-19-6-4-18(5-7-19)32-11-8-31(9-12-32)10-13-33-23-20(17-27-33)24-28-22(21-3-2-14-37-21)30-34(24)25(26)29-23/h2-7,14,17H,8-13,15-16H2,1H3,(H2,26,29)

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = DTYWJKSSUANMHD-UHFFFAOYSA-N

'''Preladenant''' (developmental code name '''SCH-420814''') is a drug that was developed by [[Schering-Plough]] which acted as a [[potency (pharmacology)|potent]] and [[binding selectivity|selective]] [[receptor antagonist|antagonist]] of the [[adenosine]] [[adenosine A2a receptor|A_2A receptor]].<ref name="SalamoneCorreaFerrigno2018">{{cite journal | vauthors = Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE | title = The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation | journal = Pharmacol Rev | volume = 70 | issue = 4 | pages = 747–762 | date = October 2018 | pmid = 30209181 | pmc = 6169368 | doi = 10.1124/pr.117.015107 | url = }}</ref> It was being researched as a potential treatment for [[Parkinson's disease]].<ref name="pmid19332567">{{cite journal | vauthors = Hodgson RA, Bertorelli R, Varty GB, Lachowicz JE, Forlani A, Fredduzzi S, Cohen-Williams ME, Higgins GA, Impagnatiello F, Nicolussi E, Parra LE, Foster C, Zhai Y, Neustadt BR, Stamford AW, Parker EM, Reggiani A, Hunter JC | display-authors = 6 | title = Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 330 | issue = 1 | pages = 294–303 | date = July 2009 | pmid = 19332567 | doi = 10.1124/jpet.108.149617 | s2cid = 22033475 }}</ref> Positive results were reported in Phase II [[clinical trials]] in humans,<ref>{{cite journal | vauthors = Hauser RA, Cantillon M, Pourcher E, Micheli F, Mok V, Onofrj M, Huyck S, Wolski K | display-authors = 6 | title = Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial | journal = The Lancet. Neurology | volume = 10 | issue = 3 | pages = 221–229 | date = March 2011 | pmid = 21315654 | doi = 10.1016/S1474-4422(11)70012-6 | s2cid = 39226234 }}</ref> but it did not prove itself to be more effective than a placebo during Phase III trials, and so was discontinued in May 2013.<ref>{{Cite web |url=http://bigstory.ap.org/article/merck-ends-development-parkinsons-disease-drug |title=Merck ends development of Parkinson's disease drug |access-date=2013-05-23 |archive-date=2013-06-16 |archive-url=https://archive.today/20130616142742/http://bigstory.ap.org/article/merck-ends-development-parkinsons-disease-drug |url-status=dead | work = The Big Story | publisher = Associated Press | date = 23 May 2013 }}</ref>

The drug has very high [[affinity (pharmacology)|affinity]] for the A_2A receptor (<1{{nbsp}}nM) and shows more than 1,000-fold [[binding selectivity|selectivity]] for the A_2A receptor over the other [[adenosine receptor]]s.<ref name="SalamoneCorreaFerrigno2018" /><ref name="KhayatHanifGeldenhuys2019">{{cite book | vauthors = Khayat MT, Hanif A, Geldenhuys WJ, Nayeem MA | chapter = Adenosine Receptors and Drug Discovery in the Cardiovascular System | pages=16–64 | veditors=Choudhary MI | title=Frontiers in Cardiovascular Drug Discovery: Volume 4 | publisher=Amazon Digital Services LLC - Kdp | series=Frontiers in Cardiovascular Drug Discovery | year=2019 | isbn=978-1-68108-400-8 | url=https://books.google.com/books?id=R6SXDwAAQBAJ&pg=PA16 | access-date=23 September 2024}}</ref>

Preladenant shows [[pro-motivational agent|pro-motivational]] effects in animals and reverses [[tetrabenazine]]-induced [[motivational disorder|motivational deficit]]s.<ref name="SalamoneCorreaFerrigno2018" /><ref name="TreadwaySalamone2022">{{cite journal | vauthors = Treadway MT, Salamone JD | title = Vigor, Effort-Related Aspects of Motivation and Anhedonia | journal = Curr Top Behav Neurosci | volume = 58 | issue = | pages = 325–353 | date = 2022 | pmid = 35505057 | doi = 10.1007/7854_2022_355 | url = | quote = Adenosine A2A receptor antagonists have been studied for their potential antiparkinsonian effects (Ferré 1997; Morelli and Pinna 2002; Correa et al. 2004), and istradefylline (Nourianz) has been approved for use in several countries. Particularly relevant for the present review, drugs that act on adenosine A2A receptors induce substantial effects on instrumental behavior and effort-related choice. [...] Caffeine, theophylline, and several adenosine A2A receptor antagonists (MSX-3, MSX-4, Lu AA47070, istradefylline) can reverse the low-effort bias induced by systemically administered DA D2 antagonists (Farrar et al. 2007; Worden et al. 2009; Mott et al. 2009; Collins et al. 2012; Nunes et al. 2010; Santerre et al. 2012; Randall et al. 2012; Pardo et al. 2020), and MSX-3 and preladenant reverse the effects of TBZ (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018). [...] Furthermore, A2A receptor knockout mice are resistant to the effort-related effects of haloperidol (Pardo et al. 2012). [...] Along with adenosine A2A antagonists such as istradefylline and preladenant (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018), and D1 agonists (Yohn et al. 2015b), atypical DAT inhibitors offer promise as potential treatments for effort-related motivational symptoms.}}</ref> Other A_2A receptor antagonists, including [[istradefylline]], [[Lu AA47070]], [[MSX-3]], and [[MSX-4]], have also shown such effects.<ref name="SalamoneCorreaFerrigno2018" /><ref name="TreadwaySalamone2022" /> These agents may be useful in the treatment of [[motivational disorder]]s in humans.<ref name="SalamoneCorreaFerrigno2018" /><ref name="TreadwaySalamone2022" /> Accordingly, istradefylline has been reported to reduce [[apathy]], [[anhedonia]], [[fatigue (medical)|fatigue]], and [[depression (mood)|depression]] in people with [[Parkinson's disease]].<ref name="TurnerHusain2022">{{cite journal | vauthors = Turner V, Husain M | title = Anhedonia in Neurodegenerative Diseases | journal = Curr Top Behav Neurosci | volume = 58 | issue = | pages = 255–277 | date = 2022 | pmid = 35435648 | doi = 10.1007/7854_2022_352 | url = | quote = Recently, PD patients have been treated with istradefylline, an adenosine A2A receptor antagonist used for treatment of motor symptoms. The drug was given to 14 PD patients for 12 weeks, measuring anhedonia, apathy and depression using the SHAPS, Apathy Scale and BDI. On istradefylline, SHAPS, Apathy Scale and BDI scores significantly reduced from baseline scores at 4-, 8- and 12-weeks, with mean SHAPS scores at week 12 about 50% reduced from baseline scores, indicating that istradefylline reduces anhedonia (Nagayama et al. 2019). As apathy and depression rates dropped as well as anhedonia, this trial also provided evidence for the overlapping relationship between the three symptoms. [...] Taken together, there is some evidence that dopamine agonists such as pramipexole and piribedil, or the adenosine A2A receptor antagonist istradefylline can improve anhedonia and apathy in PD.}}</ref><ref name="SalamoneCorreaFerrigno2018" />

==References==

{{Adenosine receptor modulators}}

[[Category:2-Furyl compounds]]

[[Category:Abandoned drugs]]

[[Category:Adenosine receptor antagonists]]

[[Category:Phenol ethers]]

[[Category:Piperazines]]

[[Category:Pro-motivational agents]]