H₃ receptor;
Human Histamine H3 Receptor (H3R): Antagonist/Inverse agonist. [1], [2], [4]
Rat Histamine H3 Receptor (H3R): Antagonist/Inverse agonist. [1]

In a functional [³⁵S]GTPγS binding assay using CHO cell membranes expressing the human H3 receptor, Bavisant potently inhibited R-α-methylhistamine (RAMH)-induced binding, with a Kb value of 0.4 ± 0.1 nM. It also decreased basal activity with an EC50 of 1.1 ± 0.0 nM, demonstrating full inverse agonist activity. [1]
In the same functional assay using membranes expressing the rat H3 receptor, Bavisant inhibited RAMH-induced binding with a Kb value of 1.0 ± 0.2 nM and decreased basal activity with an EC50 of 2.0 ± 0.8 nM. [1]

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In primary rat oligodendrocyte precursor cell (OPC) cultures, treatment with Bavisant at 1 μM significantly increased the number of differentiated Sox10+MBP+ oligodendrocytes compared to the basal condition (fold increase ranging from 1.24 to 2.93). [5]
In human induced pluripotent stem cell (iPSC)-derived OPC (hiOPC) cultures, Bavisant at 1 μM promoted differentiation into MBP+ oligodendrocytes. This activity was observed across three different hiPSC lines. [5]
In human fetal OPC (hfOPC) cultures, Bavisant at 1 μM for 14 days significantly increased the number of Olig2+CC1+GalC+ sheath-forming human oligodendrocytes compared to the basal condition. [5]
In a nanofiber assay using adult human A2B5+ progenitor cells, Bavisant significantly enhanced the percentage of O4+ cells forming ensheathment around nanofibers compared to the basal condition. [5]
In primary rat OPCs under differentiation conditions, Bavisant treatment led to increased expression of myelin protein genes including Mbp, Mag, Mebp, Cnp, and Mog (FDR < 0.05). [5]
Hrh3 mRNA expression in rat primary OPC cultures increased by 2- and 3.5-fold at 3 and 5 days after induction of differentiation, respectively, compared to proliferative conditions. [5]

In the rat dipsogenia model, Bavisant dose-dependently inhibited RAMH-induced water drinking. When administered intraperitoneally (i.p.) 15 minutes prior to RAMH, it showed an ED50 of 0.01 (0.001 - 0.08) mg/kg. When administered orally (p.o.), it had an ED50 of 0.06 (0.01 - 0.3) mg/kg. [1]
In a randomized, double-blind, placebo- and active-controlled, parallel-group, multicenter Phase IIb study in adults with ADHD (NCT00880217), Bavisant did not display significant clinical effectiveness. The mean change from baseline in the ADHD-RS-IV total score at day 42 (primary endpoint) was -8.8 for placebo, and -9.3, -11.2, and -12.2 for the bavisant 1 mg/day, 3 mg/day, and 10 mg/day groups, respectively. The improvement in the 10 mg/day group was not statistically superior to placebo (p = 0.161). [2]

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Bavisant dihydrochloride hydrate raises the levels of acetylcholine in the rat frontal cortex[4].
In the lysophosphatidylcholine (LPC)-induced demyelination mouse model, oral administration of Bavisant (30 mg/kg) daily from 3 days post-injection (dpi) significantly increased the number of differentiated Olig2+CC1+ oligodendrocytes in lesions at 7 dpi (p < 0.01) and 15 dpi (p < 0.05). Electron microscopy analysis at 15 dpi showed a significant increase in the percentage of remyelinated axons (p < 0.001) and a significant decrease in the G-ratio of remyelinated axons (p < 0.0001) in bavisant-treated mice compared to vehicle. [5]
In the cuprizone-induced chronic demyelination model, Bavisant treatment (30 mg/kg, oral) during the recovery phase (1-2 weeks) significantly increased the number of NogoA+ oligodendrocytes at 2 weeks recovery compared to vehicle (p < 0.05). Electron microscopy analysis also showed a significant increase in the percentage of myelinated axons after 2 weeks of recovery (p < 0.01). [5]
In a humanized chimeric mouse model (Shiverer:Rag2 mice) with human OPCs grafted into LPC-induced spinal cord lesions, Bavisant treatment (30 mg/kg, oral) significantly increased the percentage of Olig2+STEM101+ human cells and Olig2+CC1+ human oligodendrocytes at 8 and 10 weeks post-grafting. Electron microscopy confirmed a significant increase in the percentage of axons remyelinated by human cells (p < 0.05) and a significant decrease in the G-ratio of these remyelinated axons (p < 0.0001). [5]
In the MOG-induced experimental autoimmune encephalomyelitis (EAE) model, Bavisant treatment (30 mg/kg, oral, daily) initiated at the chronic phase (42 dpi) showed a trend towards reduced axonal damage in the spinal cord at 56 dpi, as measured by SMI-32 immunoreactivity, but did not improve clinical scores. In a preventive protocol (treatment started at 7 dpi), bavisant treatment delayed disease onset and reduced the maximum clinical score. [5]

Rat Primary OPC Differentiation Assay: Primary rat OPCs were cultured in differentiation medium with or without test compounds at 1 μM for 5 days. 9-cis-retinoic acid (9-cis-RA) was used as a positive control. Cells were fixed and immunostained for Sox10 (a pan-oligodendroglial marker) and MBP (a marker of mature oligodendrocytes). The number of Sox10+MBP+ cells was quantified to assess differentiation. Studies were performed in three independent experiments with triplicates for each compound. [5]
Human iPSC-Derived OPC (hiOPC) Differentiation Assay: hiOPCs were differentiated for 5 days in the presence of T3 (positive control) or test compounds at 1 μM. Cells were then fixed and immunostained for MBP. The effect on differentiation was quantified by counting MBP+ cells. Three different hiPSC lines were used for the experiments. [5]
Human Fetal OPC (hfOPC) Differentiation Assay: hfOPCs were differentiated for 14 days in glial differentiation medium with T3 (positive control) or test compounds (1 μM). Cells were immunostained for Olig2, CC1, and GalC. The number of Olig2+CC1+ cells with GalC+ pseudo-myelin sheaths was quantified as a measure of differentiation. [5]
Nanofiber Myelination Assay: Adult human A2B5+ progenitor cells were plated on nanofibers and cultured in differentiation medium for 2 weeks in the presence of vehicle (DMSO) or test compounds (500 nM). Cultures were immunostained for O4. The percentage of O4+ cells forming membrane ensheathment around nanofibers was quantified. [5]
Mechanistic Hrh3 Knockdown in Rat OPCs: Rat primary OPCs were transduced with lentivirus expressing shRNA targeting Hrh3 or a control shRNA. After 3 days of differentiation, cells were treated with or without Bavisant (1 or 10 μM). Silencing of Hrh3 increased the number of Sox10+MBP+ cells, and the addition of bavisant did not further increase this number, indicating that bavisant's effect is mediated through Hrh3. [5]

Rat Dispogenia Model: Water intake induced by the H3-selective agonist RAMH was measured in Harlan Long Evans rats for 30 minutes, beginning 20 minutes after RAMH administration (10 mg/kg, i.p.). Test compound (Bavisant) was administered in saline at indicated times prior to the drinking trial. The percent inhibition of RAMH-induced drinking was calculated. [1]
Rat Pharmacokinetic Study: For detailed PK parameters, rats were administered Bavisant at 1 mg/kg intravenously (i.v.) and 3 mg/kg orally (p.o.) in saline. Serial blood samples were collected from the lateral tail vein over a 6 or 24-hour period. The plasma was separated and analyzed by LC-MS/MS. Pharmacokinetic parameters were calculated by a noncompartmental method. [1]
Mouse LPC Demyelination Model: Demyelination was induced by injecting LPC into the dorsal funiculus of the mouse spinal cord. Bavisant (30 mg/kg) or vehicle (0.5% methylcellulose) was administered daily by oral gavage starting from 3 days post-injection (dpi) until euthanasia at 7 or 15 dpi. Spinal cords were processed for immunohistochemistry and electron microscopy. [5]
Mouse Cuprizone Demyelination Model: Mice were fed a diet containing 0.2% cuprizone for 10 weeks to induce demyelination. During the recovery phase (1-2 weeks after cuprizone withdrawal), mice were treated daily with Bavisant (30 mg/kg, oral gavage) or vehicle (0.5% methylcellulose). Brains were processed for immunohistochemistry and electron microscopy. [5]
Humanized Chimeric Mouse Model (Shiverer:Rag2): Human fetal OPCs were grafted into LPC-induced lesions in the spinal cord of Shiverer:Rag2 immunodeficient mice. From 5 weeks post-grafting (wpg) until euthanasia at 10 wpg, mice received daily oral administration of Bavisant (30 mg/kg) or vehicle (0.5% methylcellulose). Spinal cords were processed for immunohistochemistry and electron microscopy. [5]
MOG-Induced EAE Model: Chronic EAE was induced in mice by immunization with MOG35-55 peptide. In the chronic treatment protocol, mice received daily oral doses of Bavisant (30 mg/kg) or vehicle starting at 42 dpi until 56 dpi. In the preventive protocol, treatment started at 7 dpi. Clinical scores were recorded daily. Spinal cords were collected at 56 dpi for analysis of axonal damage (SMI-32 immunostaining). [5]

In Rat: Following i.v. administration (1 mg/kg), Bavisant showed a terminal half-life (t1/2) of 2.6 h, high systemic clearance (42 (mL/min)/kg), a high volume of distribution (Vd) of 9.4 L/kg, and high oral bioavailability (F = 83%) after p.o. administration (3 mg/kg). The brain-to-plasma ratio (B/P) was 2.6. [1]
In Dog: Following i.v. administration (1 mg/kg), Bavisant showed a t1/2 of 2.9 h, clearance (CL) of 13.2 ± 1.5 (mL/min)/kg, and an oral bioavailability of 22 ± 2% (3 mg/kg, p.o.). The B/P ratio was 2.4 ± 0.4. [1]
In Monkey: Following i.v. administration (1 mg/kg), Bavisant showed a t1/2 of 5.4 h, a Vd of 3.8 ± 0.9 L/kg, a CL of 7.7 ± 1.8 (mL/min)/kg, and an oral bioavailability of 83 ± 18% (1 mg/kg, p.o.). [1]
In Mouse: After oral administration of Bavisant (30 mg/kg) in 0.5% methylcellulose, the average unbound brain-to-plasma ratio was determined to be >1, indicating good passive brain penetration. Unbound brain concentrations were above the human HRH3 Ki for up to 24 hours post-dose. [5]

In Clinical Trial for ADHD (NCT00880217): In a Phase IIb study, the incidence of treatment-emergent adverse events (TEAEs) was 61.8%, 82.4%, and 89.0% for Bavisant 1, 3, and 10 mg/day groups, respectively, compared to 58.9% for placebo. Discontinuations due to TEAEs were 4.4%, 7.4%, and 19.2% for the 1, 3, and 10 mg/day groups, respectively, versus 2.7% for placebo. Common TEAEs (≥5%) showed a dose-dependent pattern and included middle insomnia, initial insomnia, nausea, abnormal dreams, insomnia, dizziness, and dysgeusia. Sleep-related TEAEs occurred in 27.9%, 50.0%, and 67.1% of patients receiving 1, 3, and 10 mg/day, respectively, compared to 13.7% for placebo. The incidence of cardiovascular-related TEAEs was 2.9%, 7.4%, and 9.6% for the 1, 3, and 10 mg/day groups, respectively, versus 4.1% for placebo. One serious adverse event (intervertebral disc protrusion) led to treatment discontinuation in the 10 mg/day group. No deaths occurred. [2]
Plasma Protein Binding: Bavisant (referenced as 8a) was only minimally bound to plasma proteins of rat (39%), dog (32%), and human (44%) in vitro. [1]
hERG Channel Inhibition: The hERG current IC50 for Bavisant (referenced as 8a) was 13.8 ± 0.8 μM. [1]
CYP450 Inhibition: Bavisant (referenced as 8a) inhibited CYP1A2, 2C9, 2C19, 2D6, and 3A4 with IC50 values greater than 30 μM, indicating minimal potential for drug-drug interactions. [1]

[1]. Discovery and characterization of 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, irdabisant): a potent, selective histamine H3 receptor inverse agonist. J Med Chem. 2011 Jul 14;54(13):4781-92.

[2]. Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder. CNS Drugs. 2012 May 1;26(5):421-34.

[3]. Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents. Eur J Med Chem. 2018 May 25;152:148-159.

[4]. Histamine H3 receptor antagonists/inverse agonists: Where do they go? Pharmacol Ther. 2019 Aug;200:69-84.

[5]. In silico screening and preclinical validation identify bavisant as a therapeutic candidate for multiple sclerosis. Sci Transl Med. 2026 Jan 21;18(833):eads0633.

Bavisant is the diamine (4-cyclopropylpiperazin-1-yl)-(4-morpholin-4-ylmethylphenyl)methanone (1e, JNJ-31001074). At the time of the 2011 publication, it had completed a Phase II ADHD trial, but results were not reported. [1]
It is a CNS-penetrable compound with favorable pharmacokinetic properties, including good passive brain penetration as shown by an unbound brain-to-plasma ratio >1 in mice. [5]
Bavisant (JNJ-31001074) has been investigated in several clinical trials, including Phase I studies in healthy volunteers to evaluate pharmacokinetics, the effect of food, and drug interactions, as well as Phase II studies for ADHD in adults and children and for excessive daytime sleepiness in Parkinson's disease. [4]
The neuroprotective and promyelinating effects of Bavisant identified in preclinical models of MS suggest its potential as a candidate for early-phase intervention, possibly complementing existing immunomodulatory therapies. [5]

C19H31CL2N3O3

420.37374329567

419.174

C, 54.29; H, 7.43; Cl, 16.87; N, 10.00; O, 11.42

1103522-80-0

Bavisant; 929622-08-2; Bavisant dihydrochloride; 929622-09-3

56843503

White to pink solid powder

2.792

3

5

4

27

418

0

O=C(N1CCN(C2CC2)CC1)C(C=C3)=CC=C3CN4CCOCC4.[H]Cl.[H]Cl.O

BLFBQJUVAGIUBL-UHFFFAOYSA-N

InChI=1S/C19H27N3O2.2ClH.H2O/c23-19(22-9-7-21(8-10-22)18-5-6-18)17-3-1-16(2-4-17)15-20-11-13-24-14-12-20;;;/h1-4,18H,5-15H2;2*1H;1H2

(4-cyclopropylpiperazin-1-yl)-[4-(morpholin-4-ylmethyl)phenyl]methanone;hydrate;dihydrochloride

Bavisant dihydrochloride hydrate; JNJ-31001074-AAC; BAVISANT; 929622-08-2; JNJ-31001074; 9827P7LFVH; DTXSID001026045; JNJ 31001074-AAC; JNJ-31001074 dihydrochloride hydrate; JNJ31001074 dihydrochloride hydrate; JNJ 31001074;JNJ31001074-AAC

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O: ≥ 50 mg/mL (~118.9 mM)
DMSO: ≥ 1 mg/mL (~2.4 mM)

Solubility in Formulation 1: 50 mg/mL (118.94 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)