JNJ-42165279: Current Research and Potential Applications

JNJ-42165279 is a compound of interest in pharmacological research due to its potential effects on the endocannabinoid system and fatty acid amide pathways. Scientists are investigating its role in modulating biochemical processes relevant to therapeutic applications, particularly in pain management and inflammation.

Understanding its interactions with biological systems requires examining its chemical properties, metabolic behavior, and mechanisms of action. Researchers use various analytical techniques to study its effects at molecular and systemic levels.

Chemical Composition

JNJ-42165279 is a small-molecule inhibitor targeting fatty acid amide hydrolase (FAAH), an enzyme responsible for degrading bioactive lipids. Its chemical structure is optimized for high selectivity and potency, incorporating functional groups that enhance binding affinity to FAAH’s active site. The molecular formula and atomic arrangement contribute to its stability and bioavailability, key factors in its pharmacological efficacy.

The compound features a fluorinated aromatic ring, which enhances lipophilicity and metabolic resistance. Fluorine substitution improves membrane permeability and reduces enzymatic breakdown. Additionally, JNJ-42165279 contains an amide linkage that facilitates interactions with FAAH’s catalytic residues, prolonging its inhibitory action. This amide bond is strategically positioned to enhance molecular recognition and ensure strong, sustained engagement with the enzyme.

Heterocyclic elements in JNJ-42165279 contribute to its pharmacokinetic profile. Heterocycles are often used in drug design to fine-tune solubility and receptor binding. In this case, nitrogen-containing rings optimize FAAH interaction while minimizing off-target effects. These structural refinements balance potency and safety.

Role In Fatty Acid Amide Pathways

JNJ-42165279 modulates fatty acid amide pathways, a biochemical network regulating neurotransmission, pain perception, and cellular homeostasis. These pathways involve bioactive signaling molecules known as fatty acid amides (FAAs), including anandamide (AEA), oleamide, and palmitoylethanolamide (PEA). FAAH, a membrane enzyme, hydrolyzes these lipid messengers, limiting their biological activity. By inhibiting FAAH, JNJ-42165279 increases FAA levels, prolonging their effects and altering downstream signaling.

Anandamide, a well-studied FAA, binds to cannabinoid receptors CB1 and CB2 in the central nervous system and peripheral tissues. FAAH normally degrades anandamide, curtailing receptor interaction. JNJ-42165279 blocks this degradation, increasing anandamide concentrations and sustaining receptor activation. Studies have shown FAAH inhibitors enhance anandamide-mediated signaling, producing analgesic and neuroprotective effects. Research published in The Journal of Pharmacology and Experimental Therapeutics demonstrated that FAAH inhibition prolonged anandamide activity, reducing nociceptive responses in rodent models of inflammatory pain.

Beyond anandamide, JNJ-42165279 influences other FAAs such as PEA and oleamide. PEA interacts with peroxisome proliferator-activated receptor-alpha (PPAR-α), a nuclear receptor involved in inflammation and metabolism. By preventing PEA breakdown, JNJ-42165279 enhances PPAR-α activation, linked to anti-inflammatory and neuroprotective benefits. Experimental models of neurodegeneration have shown FAAH inhibition mitigates glial activation and oxidative stress. Similarly, increased oleamide availability following FAAH inhibition has been associated with improved sleep architecture in animal studies.

Pharmacokinetics And Metabolism

The absorption, distribution, metabolism, and excretion (ADME) profile of JNJ-42165279 is crucial for its therapeutic viability. The compound exhibits high oral bioavailability due to its lipophilic nature and fluorinated aromatic ring, which facilitate passive diffusion across membranes for efficient gastrointestinal absorption. Once in circulation, it demonstrates moderate plasma protein binding, affecting its free concentration and systemic availability.

JNJ-42165279 distributes extensively into tissues with high FAAH expression, including the brain. Preclinical studies using radiolabeled analogs confirm its ability to cross the blood-brain barrier efficiently, distinguishing it from peripherally restricted FAAH inhibitors. This CNS accessibility enhances its therapeutic potential for neurological and pain-related conditions but also requires careful consideration of central adverse effects. The compound’s volume of distribution (Vd) suggests significant extravascular distribution, estimated in preclinical pharmacokinetic modeling to be in the range of 5–10 L/kg.

Metabolism primarily occurs in the liver, where cytochrome P450 enzymes mediate phase I biotransformation. Oxidative metabolism, particularly hydroxylation and N-dealkylation, generates inactive and minimally active metabolites. Studies using human liver microsomes identify CYP3A4 and CYP2D6 as key enzymes in its metabolism, raising potential drug-drug interaction concerns. Phase II conjugation processes, including glucuronidation, enhance water solubility for renal and biliary excretion. The terminal elimination half-life, estimated between 6 and 12 hours in preclinical models, suggests a dosing regimen that balances sustained FAAH inhibition with manageable accumulation risk.

Endocannabinoid System Interactions

JNJ-42165279 influences the endocannabinoid system (ECS) by modulating endogenous cannabinoids, particularly anandamide. The ECS consists of cannabinoid receptors (CB1 and CB2), endogenous ligands, and enzymes regulating their availability. CB1 receptors, found in the brain and spinal cord, influence neurotransmitter release, while CB2 receptors are prevalent in peripheral tissues involved in immune and inflammatory responses. By inhibiting FAAH, JNJ-42165279 increases anandamide levels, prolonging receptor activation and altering synaptic signaling.

Preclinical research focuses on JNJ-42165279’s effects on CB1 receptor activity in pain modulation and emotional regulation. Unlike direct CB1 agonists, which can induce psychoactive effects and tolerance, FAAH inhibition provides a more regulated increase in anandamide signaling. This indirect activation mechanism results in localized and transient receptor engagement, reducing the risk of adverse effects associated with excessive CB1 stimulation. Research published in Neuropharmacology highlights how FAAH inhibition enhances anandamide’s anxiolytic and analgesic properties without the cognitive impairments observed with synthetic cannabinoids.

Laboratory Methods For Analysis

Investigating JNJ-42165279’s pharmacological properties requires precise analytical techniques to quantify its concentration, assess its metabolic profile, and evaluate biochemical interactions. Researchers use chromatographic, spectrometric, and immunoassay-based methodologies to characterize the compound in biological matrices.

Chromatographic and Spectrometric Techniques

High-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (LC-MS/MS) is the primary method for detecting and quantifying JNJ-42165279 in plasma, cerebrospinal fluid, and tissue samples. LC-MS/MS provides high sensitivity and specificity, enabling precise measurement of the parent compound and its metabolites. Researchers optimize mobile phase compositions and column chemistries for optimal resolution, ensuring reliable analyte separation. Gas chromatography-mass spectrometry (GC-MS) is also used to analyze volatile metabolites formed through oxidative pathways. Advanced derivatization techniques improve detection of polar metabolites, enhancing analytical throughput in metabolic stability studies.

Biochemical and Immunoassay-Based Approaches

Enzyme activity assays assess JNJ-42165279’s inhibitory effects on FAAH. Fluorescence-based assays using fluorogenic FAAH substrates allow real-time kinetic measurements, providing insights into enzyme inhibition dynamics. Radiolabeled substrate assays enable precise FAAH activity quantification by tracking labeled metabolite release. Western blotting and immunohistochemistry assess FAAH expression levels in tissue samples, offering complementary data on how JNJ-42165279 modulates enzyme abundance. These methodologies enhance understanding of its biochemical interactions, supporting further research into its therapeutic potential.