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Purity: ≥98%
JNJ-39758979 is a novel, potent and selective, high-affinity histamine H4 receptor antagonist with a Ki of 12.5 nM. has been investigated in phase II clinical trials for atopic dermatitis and asthma. Utilizing insights from the tricyclic pyrimidines and expanding upon our SAR investigations of saturated derivatives from the indole carboxamide series, exemplified by JNJ 7777120, allowed us to arrive at the 6-alkyl-2,4-diaminopyrimidine series. Several 6-alkyl-2,4-diaminopyrimidines that acted as antagonists at the human and rodent H4 receptor were produced by a concentrated medicinal chemistry effort. A panel of antagonists that were profiled in animal models of inflammatory disease resulted from additional optimization. JNJ 39758979 was chosen as a clinical candidate based on the preclinical profile and effectiveness in multiple animal models; however, phase II development was stopped due to the discovery of drug-induced agranulocytosis (DIAG) in two subjects.
| Targets |
Human H4 Receptor ( Ki = 12.5 nM ); Mouse H4 Receptor ( Ki = 5.3 nM ); Monkey H4 receptor ( Ki = 25 nM ); Rat H4 receptor ( Ki = 188 nM ); Guinea pig H4 receptor ( Ki = 306 nM )
Histamine H4 receptor (antagonist; human H4 Ki = 12.5 nM; human H4 pA2 = 7.9) [1] JNJ-39758979 also binds to mouse H4R (Ki = 5.3 nM; pA2 = 8.3), monkey H4R (Ki = 25 nM; pA2 = 7.5), rat H4R (Ki = 188 nM; pA2 = 7.2), and guinea pig H4R (Ki = 306 nM). It has little to no affinity for dog H4R (Ki ≥ 10 µM). [1] The compound exhibits low affinity for H1, H2, and H3 receptors, and no significant cross-reactivity with a broad panel of kinases, receptors, and channels. [1] |
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| ln Vitro |
JNJ 39758979 effectively counteracts histamine-induced cAMP inhibition. It is a selective, high-affinity histamine H4 receptor antagonist with a Ki of 12.5 nM versus the human H4 receptor with a pA2 of 7.9 in transfected cells. At mouse H4R, pA2=8.3 and Ki=5.3 nM are found. At the monkey H4R, pA2=7.5 and Ki=25 nM. While JNJ 39758979 has little to no affinity for the dog H4R (Ki≥10 μM), it has a moderate affinity for the rat (Ki=188 nM, pA2 = 7.2) and guinea pig H4R (Ki=306 nM). Due to its low affinity for the H1, H2, and H3 receptors, the compound is highly selective for the H4R receptor[1].
JNJ-39758979 is metabolically stable (t1/2 >120 min) in vitro when cultured with liver microsomes from rats, dogs, or monkeys[1]. JNJ-39758979 is a selective, high-affinity histamine H4 receptor antagonist, displacing [³H] histamine from the recombinant human H4 receptor with a Ki of 12.5 nM. [1] Functionally, it antagonizes histamine-induced inhibition of forskolin-stimulated cAMP-mediated reporter gene activity in SK-N-MC cells expressing the human H4 receptor, with a pA2 of 7.9. [1] JNJ-39758979 showed no inhibition of CYP450 isozymes 3A4, 2C9, 2D6, or 1A2 at concentrations of 50–100 µM. [1] The compound did not inhibit astemizole binding to the hERG channel at concentrations up to 30 µM and showed no inhibition of the hERG-mediated K⁺ current in transfected cells at concentrations up to 10 µM. [1] JNJ-39758979 was negative in the Ames mutagenicity test. [1] The compound was metabolically stable in in vitro incubations with human, rat, dog, and monkey liver microsomes (t₁/₂ > 120 min). [1] CACO-2 permeability assay showed absorptive permeability with values of 23 × 10⁻⁶ cm/s (A->B) and 22 × 10⁻⁶ cm/s (B->A). [1] Plasma protein binding (free fraction) was 81% in human, 83% in rat, and 76% in mouse. [1] |
| ln Vivo |
JNJ-39758979 (10 mg/kg; p.o.) treatment reveals that the Cmax, t1/2, and F values are, in that order, 0.3 μM, 7.5 hours, and 36%[1].
JNJ-39758979 (2 mg/kg; i.v.) treatment reveals that the Vss, AUC, CL, and t1/2 were, in that order, 19.9 L/kg, 1.4 μMh, 2.2 L/h, and 2.1 hours [1]. JNJ-39758979 inhibited histamine-induced scratching (itch) in C57Bl/6 mice at oral doses of 5 and 20 mg/kg, to a similar extent as the reference compound JNJ 7777120. [1] In a mouse model of LPS-induced TNFα release, oral administration of JNJ-39758979 inhibited TNFα production in a dose-dependent manner, with inhibition observed when plasma concentrations were at or above the mouse H4 Ki. [1] JNJ-39758979 exhibited dose-dependent inhibition of clinical scores in a mouse collagen-induced arthritis model. [1] |
| Enzyme Assay |
The assay for histamine receptor affinity (Ki) involved displacement of [³H] histamine from recombinant histamine H4 receptors. The Ki values were calculated according to Cheng and Prusoff. [1]
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| Cell Assay |
The functional antagonism (pA2) of JNJ-39758979 was determined using SK-N-MC cells expressing the human histamine H4 receptor. Histamine inhibition of forskolin-stimulated cAMP-mediated reporter gene activity was measured. [1]
The compound was also evaluated for its ability to inhibit histamine-induced cAMP inhibition in transfected cells expressing H4 receptors from various species (human, mouse, monkey, rat, guinea pig). [1] |
| Animal Protocol |
Sprague-Dawley rats
10 mg/kg Oral administration (Pharmacokinetic Analysis) For the histamine-induced itch model, C57Bl/6 mice (n=6-8 per group) were given JNJ-39758979 orally (p.o.) in 20% hydroxypropyl-β-cyclodextran vehicle, 30 minutes before an intradermal injection of histamine (100 µg). Scratching bouts were counted over 20 minutes using an automated system. [1] For the LPS-induced TNFα model, Balb/c mice (n=7-9 per group) were dosed orally with JNJ-39758979 in 20% hydroxypropyl-β-cyclodextran, 30 minutes before intraperitoneal (i.p.) administration of LPS (200 µL of 0.1 mg/mL). Plasma was collected 2 hours later for TNFα quantification by ELISA. [1] For the collagen-induced arthritis model, compounds were dosed orally in 20% hydroxypropyl-β-cyclodextran. Clinical scores were monitored over time. [1] Pharmacokinetic studies were conducted in mice, rats, and dogs. For oral dosing, JNJ-39758979 was formulated in 20% hydroxypropyl-β-cyclodextran. Specific doses varied (e.g., 2-500 mg/kg in rats). [1] |
| ADME/Pharmacokinetics |
In Balb/c mice, after intravenous administration of a 2 mg/kg dose, the clearance (Cl) of JNJ-39758979 was 2.4 L/h/kg, the steady-state volume of distribution (Vss) was 31.0 L/kg, and the half-life (t₁/₂) was 7.8 h. The oral bioavailability (F) was 84% at a 5 mg/kg dose and 75% at a 20 mg/kg dose. [1] In Sprague-Dawley rats, after intravenous administration of a 2 mg/kg dose, the Cl was 5.5 L/h/kg, the Vss was 19.9 L/kg, and the t₁/₂ was 2.1 h. The oral bioavailability was 35% to 53% in the dose range of 10 to 500 mg/kg. [1] In beagles, the clearance (Cl) after intravenous administration of a 2 mg/kg dose was 1.4 L/h/kg, the steady-state volume of distribution (Vss) was 19.9 L/kg, and the half-life (t₁/₂) was 10.2 h. The bioavailability at an oral dose of 10 mg/kg was 95%. [1] Tissue distribution studies in mice after oral administration of a 5 mg/kg dose showed that the distribution to the brain was slower than that to the liver and kidneys (mean tmax = 20 h) (mean tmax = 60 h). Elimination from tissues was also slower, with half-lives (t₁/₂) of 42.5 h for the brain, 22.3 h for the liver, and 20.5 h for the kidneys. The tissue/plasma ratios were higher in the liver and kidneys (from 23.2 to 95.8), while the tissue/plasma ratio in the brain increased over time (from 0.256 to 22.7 over 48 hours). [1]
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| Toxicity/Toxicokinetics |
JNJ-39758979 showed good tolerability in rats and dogs in tolerability studies, and no systemic toxicity risk was identified during preclinical evaluation. [1]
However, in a phase II clinical trial for asthma and atopic dermatitis, two subjects developed drug-induced agranulocytosis (DIAG), leading to the termination of subsequent clinical development. [1] The compound was negative in the Ames test. [1] At concentrations up to 100 µM, the compound did not show inhibitory activity against major human CYP450 isoenzymes (3A4, 2C9, 2D6, 1A2). [1] No significant inhibitory activity against hERG channels was observed at the tested concentrations. [1] |
| References |
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| Additional Infomation |
JNJ-39758979 was initially discovered as a series of 6-alkyl-2,4-diaminopyrimidine histamine H4 receptor antagonists. [1] Based on its desirable in vitro properties, pharmacokinetic properties, and efficacy in animal models of various inflammatory diseases (pruritus, LPS-induced TNFα release, collagen-induced arthritis), JNJ-39758979 was selected as a clinical candidate. [1] JNJ-39758979 has entered a Phase II clinical trial for asthma and atopic dermatitis (ClinicalTrials.gov registration number: NCT01497119). [1] The Phase II clinical trial development of this drug was forced to be suspended due to the observation of drug-specific agranulocytosis (DIAG) in two subjects. It is speculated that its mechanism may involve off-target effects, perhaps through the formation of active metabolites. [1]
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| Molecular Formula |
C11H19N5
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|---|---|
| Molecular Weight |
221.302061319351
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| Exact Mass |
221.164
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| Elemental Analysis |
C, 59.70; H, 8.65; N, 31.65
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| CAS # |
1046447-90-8
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| Related CAS # |
1620648-30-7 (HCl salt)
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| PubChem CID |
24994634
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
439.6±55.0 °C at 760 mmHg
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| Flash Point |
219.6±31.5 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.594
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| LogP |
-0.18
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
16
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| Complexity |
232
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1(N)=NC(C(C)C)=CC(N2CC[C@@H](N)C2)=N1
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| InChi Key |
COOGVHJHSCBOQT-MRVPVSSYSA-N
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| InChi Code |
InChI=1S/C11H19N5/c1-7(2)9-5-10(15-11(13)14-9)16-4-3-8(12)6-16/h5,7-8H,3-4,6,12H2,1-2H3,(H2,13,14,15)/t8-/m1/s1
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| Chemical Name |
4-[(3R)-3-aminopyrrolidin-1-yl]-6-propan-2-ylpyrimidin-2-amine
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| Synonyms |
JNJ-39758979; JNJ 39758979; JNJ39758979
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~33.3 mg/mL (~150.6 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.5 mg/mL (15.82 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 35.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3.5 mg/mL (15.82 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 35.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3.5 mg/mL (15.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.5188 mL | 22.5938 mL | 45.1875 mL | |
| 5 mM | 0.9038 mL | 4.5188 mL | 9.0375 mL | |
| 10 mM | 0.4519 mL | 2.2594 mL | 4.5188 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01442545 | Completed | Drug: JNJ-39758979 / MTX | Rheumatoid Arthritis | Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
August 2011 | Phase 1 |
| NCT01081821 | Completed | Drug: single dose NJ-39758979/ matching placebo Drug: multi-dose JNJ-39758979 / matching placebo |
Healthy | Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
February 2010 | Phase 1 |
| NCT01068223 | Completed | Drug: A: JNJ-39758979/Placebo #1 Drug: C:Cetirizine/JNJ-39758979 Matching Placebo |
Histamine Induced Itch | Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
February 2010 | Phase 1 |
| NCT00946569 | Completed | Drug: JNJ39758979 Drug: Placebo |
Asthma | Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
August 2009 | Phase 2 |
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