Pimavanserin

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Pimavanserin
Pimavanserin structure.svg
Systematic (IUPAC) name
N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide
Clinical data
Trade names Nuplazid
Routes of
administration
Oral (tablets)
Legal status
Legal status
Pharmacokinetic data
Protein binding 94–97%[1]
Metabolism Hepatic (CYP3A4, CYP3A5, CYP2J2)[2]
Biological half-life 54–56 hours[1]
Identifiers
CAS Number 706779-91-1 YesY
706782-28-7 (tartrate)
ATC code None
PubChem CID 10071196
DrugBank DB05316
ChemSpider 8246736 N
UNII JZ963P0DIK YesY
KEGG D08969
ChEMBL CHEMBL2111101
Synonyms ACP-103
Chemical data
Formula C25H34FN3O2
Molar mass 427.553 g/mol
 NYesY (what is this?)  (verify)

Pimavanserin (INN), or pimavanserin tartate (USAN), marketed under the trade name Nuplazid, is a non-dopaminergic atypical antipsychotic[2] developed by Acadia Pharmaceuticals for the treatment of Parkinson's disease psychosis and schizophrenia. Pimavanserin has a unique mechanism of action relative to other antipsychotics, behaving as a selective inverse agonist of the serotonin 5-HT2A receptor, with 40-fold selectivity for this site over the 5-HT2C receptor and no significant affinity or activity at the 5-HT2B receptor or dopamine receptors.[1] The drug has met expectations for a Phase III clinical trial for the treatment of Parkinson's disease psychosis,[3] and has completed Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[4]

Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics.[5][6][7] The results of a clinical trial examining the efficacy, tolerability and safety of adjunctive pimavanserin to risperidone and haloperidol were published in November 2012, and the results showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses of risperidone and improved the tolerability of haloperidol treatment by reducing the incidence of extrapyramidal symptoms.[8]

On September 2, 2014, the United States Food and Drug Administration granted Breakthrough Therapy status to Acadia's New Drug Application for pimavanserin.[9] It was approved by the FDA to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson's disease on April 29, 2016.[10]

Clinical pharmacology[edit]

Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding affinity (Ki 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki 0.44 nM). Pimavanserin shows low binding to σ1 receptors (Ki 120 nM) and has no appreciable affinity (Ki >300 nM) to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels.[2]

External links[edit]

References[edit]

  1. ^ a b c Friedman, JH (October 2013). "Pimavanserin for the treatment of Parkinson’s disease psychosis". Expert Opinion on Pharmacotherapy 14 (14): 1969–1975. doi:10.1517/14656566.2013.819345. PMID 24016069. 
  2. ^ a b c "Nuplazid (pimavanserin) Tablets, for Oral Use. U.S. Full Prescribing Information" (PDF). ACADIA Pharmaceuticals Inc. Retrieved 1 May 2016. 
  3. ^ ACADIA Pharmaceuticals. "Treating Parkinson's Disease - Clinical Trial Pimavanserin - ACADIA". Archived from the original on February 25, 2009. Retrieved 2009-04-11. 
  4. ^ "ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial" (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11. 
  5. ^ Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (Aug 2007). "ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models". The Journal of Pharmacology and Experimental Therapeutics 322 (2): 862–70. doi:10.1124/jpet.107.121715. PMID 17519387. 
  6. ^ Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (Oct 2008). "A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model". Pharmacology, Biochemistry, and Behavior 90 (4): 540–4. doi:10.1016/j.pbb.2008.04.010. PMC 2806670. PMID 18534670. 
  7. ^ Abbas A, Roth BL (Dec 2008). "Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders". Expert Opinion on Pharmacotherapy 9 (18): 3251–9. doi:10.1517/14656560802532707. PMID 19040345. 
  8. ^ Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (Nov 2012). "Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day". Schizophrenia Research 141 (2-3): 144–152. doi:10.1016/j.schres.2012.07.029. PMID 22954754. 
  9. ^ "ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for NUPLAZID™ (Pimavanserin) for Parkinson’s Disease Psychosis". Press Releases. Acadia. 2014-09-02. 
  10. ^ "Press Announcements — FDA approves first drug to treat hallucinations and delusions associated with Parkinson’s disease". U.S. Food and Drug Administration. Retrieved 1 May 2016.