Details
Stereochemistry | ACHIRAL |
Molecular Formula | C17H17ClN4 |
Molecular Weight | 312.797 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
ClC1=CC2=C(NC3=C(C=CC=C3)C(=N2)N4CCNCC4)C=C1
InChI
InChIKey=JNNOSTQEZICQQP-UHFFFAOYSA-N
InChI=1S/C17H17ClN4/c18-12-5-6-15-16(11-12)21-17(22-9-7-19-8-10-22)13-3-1-2-4-14(13)20-15/h1-6,11,19-20H,7-10H2
DescriptionCurator's Comment: description was created based on several sources, including
http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=1166151
Curator's Comment: description was created based on several sources, including
http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=1166151
ACP-104 or N-Desmethylclozapine (NDMC), or norclozapine is a major metabolite of clozapine, which was developed like a small molecule drug candidate by ACADIA for treatment schizophrenia. ACP-104 combines M1 muscarinic agonist, 5-HT2A inverse agonist, and D2 and D3 dopamine partial agonist in a single compound and, therefore, uniquely addresses what ACADIA believed are the three most promising target mechanisms for treating schizophrenia. Then drug was discontinued, because the study did not meet its primary endpoint of antipsychotic efficacy or any of the secondary endpoints. Neither dose of ACP-104 demonstrated improved efficacy as compared to placebo. The most common adverse events in the treatment arms relative to placebo were increased salivation, tachycardia, and dyspepsia, which were noted to be dose-related. There was no clinically significant decrease in neutrophil counts in the study drug arms.
CNS Activity
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL216 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15900318 |
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Target ID: CHEMBL217 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16135699 |
89.0 nM [IC50] | ||
Target ID: CHEMBL234 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16135699 |
14.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
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Plasma clozapine levels and the treatment of L-DOPA-induced psychosis in Parkinson's disease. A high potency effect of clozapine. | 1995 Feb |
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Metabolites of the antipsychotic agent clozapine inhibit the replication of human immunodeficiency virus type 1. | 1997 May 3 |
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Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo. | 2001 |
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Isolation and identification of clozapine metabolites in patient urine. | 2001 Jun |
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Correlation of antipsychotic and prolactin concentrations in children and adolescents acutely treated with haloperidol, clozapine, or olanzapine. | 2002 Summer |
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Pharmacokinetics of clozapine and its metabolites in hippocampal HT22 cells. | 2003 Aug 29 |
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Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. | 2003 May |
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N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. | 2003 Nov 11 |
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Differing response to antipsychotic therapy in schizophrenia: pharmacogenomic aspects. | 2004 Mar |
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Effects of clozapine and its metabolites on the 5-HT2 receptor system in cortical and hippocampal cells in vitro. | 2004 Mar |
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Field-amplified sample stacking in capillary electrophoresis for the determination of clozapine, clozapine N-oxide, and desmethylclozapine in schizophrenics' plasma. | 2004 Sep 25 |
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Increased serum S100B in elderly, chronic schizophrenic patients: negative correlation with deficit symptoms. | 2005 Dec 15 |
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Increased serum interleukin-1beta and interleukin-6 in elderly, chronic schizophrenic patients on stable antipsychotic medication. | 2005 Jun |
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Dopamine uptake inhibitor-induced rotation in 6-hydroxydopamine-lesioned rats involves both D1 and D2 receptors but is modulated through 5-hydroxytryptamine and noradrenaline receptors. | 2005 Mar |
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An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels. | 2005 May |
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High throughput therapeutic drug monitoring of clozapine and metabolites in serum by on-line coupling of solid phase extraction with liquid chromatography-mass spectrometry. | 2006 Apr 13 |
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Structural requirements of transmembrane domain 3 for activation by the M1 muscarinic receptor agonists AC-42, AC-260584, clozapine, and N-desmethylclozapine: evidence for three distinct modes of receptor activation. | 2006 Dec |
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Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs. | 2006 Oct 20 |
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Bioequivalence of clozapine orally disintegrating 100-mg tablets compared with clozapine solid oral 100-mg tablets after multiple doses in patients with schizophrenia. | 2008 |
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Massively parallel screening of the receptorome. | 2008 Jul |
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Effect of food on the pharmacokinetics of clozapine orally disintegrating tablet 12.5 mg: a randomized, open-label, crossover study in healthy male subjects. | 2009 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT00628420
Patients recieved single low or high dose of ACP-104 (NORCLOZAPINE): 25mg, 75mg, 125mg, 175mg, 225mg, or 275mg once a day for 2 weeks or 50mg, 100mg, 150mg, 200mg, 250mg, or 300mg daily for 2 weeks
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/14751426
It was determined the effects of clozapine (Cloz) and its metabolites norclozapine (Norcloz) on the 5-HT(2) receptor system on the levels of protein and gene expression in in vitro systems of primary cortical cells of the rat and human hippocampal SHS5Y5 neuroblastoma cells. A significant decrease was found in primary cortical cells for 5-HT(2) receptor density (Cloz 200/Cloz 400/Norcloz 200. 5-HT(2A) receptor mRNA levels were also significantly reduced (Norcloz 200 vs. control) in SHS5Y5 cells. GAPDH mRNA levels were not affected.
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100000174142
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64050
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DB05766
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135409468
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DESMETHYLCLOZAPINE
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1I9001LWY8
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6104-71-8
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DTXSID0042616
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C058272
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ACTIVE MOIETY
PARENT (METABOLITE ACTIVE)