General
Preferred name
pitolisant
Synonyms
BF 2649 ()
Pitolisant ()
Pitolisant (oxalate) ()
Tiprolisant oxalate ()
TIPROLISANT ()
Ciproxidine ()
Pitolisant hydrochloride ()
BF 2649 hydrochloride ()
Pitolisant (hydrochloride) ()
Tiprolisant hydrochloride, BF-2649 HCl ()
Wakix ()
HBS-101 ()
BF2.649 ()
Tiprolisant ()
Wakix, europe ()
BF-2.649 ()
BF-2649 ()
P&D ID
PD048799
CAS
903576-44-3
362665-56-3
Tags
available
drug
Approved by
EMA
FDA
First approval
2019
2016
Drug Status
investigational
approved
Drug indication
Schizophrenia
Excessive daytime sleepiness
Max Phase
Phase 4
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human histamine H3 receptor subtype [A32022]. Signalling of histaminergic neurons plays a key role in activating the arousal system with widespread projections to the whole brain [L1471] via activating orexin receptors [A32022]. Narcolepsy is characterized by insufficient neurotransmission by orexins, or hypocretins, which are excitatory peptides released by aminergic neurons from the lateral hypothalamus with widespread projections [A32025]. H3 receptors are autoreceptors that promote the re-uptake of histamine at synaptic terminals and attenuate further histamine release into the synapse [A32025]. By blocking H3 autoreceptors and increasing the levels of histamine transmitters at the synapse, pitolisant enhances the activity of brain histaminergic neurons and promotes wakefulness [L1471]. Inverse agonism of pitolisant at H3 receptors also leads to enhanced synthesis and release of endogenous histamine over the basal level [A32025].; ; Pitolisant is thought to bind to the antagonist binding site of H3 receptor, which is located within the trans-membrane core just below the extracellular loops. Piperidines forms a salt bridge with Glu206 in the membrane spanning segment and the hydroxyl of Tyr374 is H-bonded with the central oxygen of piperidine [A32025]. Pitolisant displays high selectivity for H3 receptors compared to other histamine receptor subtypes. Pitolisant also modulates acetylcholine, noradrenaline and dopamine release in the brain by increasing the levels of neurotransmitters but does not increase dopamine release in the stratal complex including nucleus accumbent [L1471].
TOXICITY Symptoms of pitolisant overdose may include headache, insomnia, irritability, nausea and abdominal pain. In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There is no clearly identified antidote [L1471].; ; After 1 month in mice, 6 months in rats and 9 months in monkeys, no adverse effect level (NOAEL) were 75, 30 and 12 mg/kg/day, p.o., respectively [L1471]. Pitolisant was not found to be genotoxic in Ames test nor carcinogenic in mouse and rat carcinogenicity studies [L1476]. In rabbit and rat teratogenicity studies, maternally high toxic doses of pitolisant sperm morphology abnormalities and decreased motility without any significant effect on fertility indexes in male rats [L1471]. It also decreased the percentage of live conceptuses and increased post-implantation loss in female rats [L1471]. A delay in post-natal development was observed [L1471].
METABOLISM Pitolisant undergoes hepatic CYP3A4- and CYP2D6-mediated metabolism to form major non-conjugated metabolites BP2.941 and BP2.951 , which are hydroxylated derivatives in several positions [L1471]. BP2.941 and BP2.951 can further be oxidized but oxidized metabolites of pitolisant such as BP1.2525 and BP1.2526 are only present to a minor extent [L1476]. Only BP1.2526 and BP1.2525 at a lesser extent have an affinity towards human H3 receptor [L1476]. The 5-aminovaleric acid is the major phase I inactive metabolite and is found in urine and serum, and its metabolism is mediated by CYP3A4 and CYP2D6 [L1471]. ; ; Several conjugated metabolites were also identified; the major conjugated inactive metabolite was a glycine conjugate of the acid metabolite of O-dealkylated desaturated pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant [L1471].
DESCRIPTION Pitolisant is a selective antagonist/inverse agonist of the histamine H3 receptor . (GtoPdb)
DESCRIPTION Potent and selective H4 antagonist (Tocris Bioactive Compound Library)
DESCRIPTION H3 receptor inverse agonist/antagonist (Tocriscreen Plus)
DESCRIPTION H3 receptor inverse agonist/antagonist (Tocriscreen Total)
Compound Sets
28
AdooQ Bioactive Compound Library
A15213
Cayman Chemical Bioactives
19307
ChEMBL Approved Drugs
CHEMBL4164059
CHEMBL462605
ChEMBL Drugs
CHEMBL4164059
CHEMBL462605
Concise Guide to Pharmacology 2017/18
8924
Concise Guide to Pharmacology 2019/20
8924
Concise Guide to Pharmacology 2021/22
8924
Concise Guide to Pharmacology 2023/24
8924
Drug Repurposing Hub
DrugBank
DB11642
DrugBank Approved Drugs
DB11642
DrugCentral
5048
DrugCentral Approved Drugs
5048
DrugMAP
DM8RFNJ
DrugMAP Approved Drugs
DM8RFNJ
EUbOPEN Chemogenomics Library
Guide to Pharmacology
8924
LSP-MoA library (Laboratory of Systems Pharmacology)
CHEMBL462605
MedChem Express Bioactive Compound Library
HY-12199B
HY-12199
NCATS Inxight Approved Drugs
4BC83L4PIY
Novartis Chemogenetic Library (NIBR MoA Box)
Other bioactive compounds
ReFrame library
Selleckchem Bioactive Compound Library
pitolisant-hydrochloride
TargetMol Bioactive Compound Library
T7176
Tocris Bioactive Compound Library
3743
Tocriscreen Plus
3743
Tocriscreen Total
External IDs
49
Properties
(calculated by RDKit )
Molecular Weight
295.17
Hydrogen Bond Acceptors
2
Hydrogen Bond Donors
0
Rotatable Bonds
8
Ring Count
2
Aromatic Ring Count
1
cLogP
4.17
TPSA
12.47
Fraction CSP3
0.65
Chiral centers
0.0
Largest ring
6.0
QED
0.67
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target Type
7-TM Receptors
Pathway
Neuronal Signaling
Immunology/Inflammation
GPCR/G protein
Neuroscience
Target
Histamine Receptor
H3 receptor
HRH3
Primary Target
Histamine H3 Receptors
MOA
Inverse Agonist
Histamine H3 Receptor Inverse Agonists
Histamine H3 Receptor Antagonists
Histamine Receptor antagonist
Member status
member
Source data