JNJ-10450232 (NTM-006) is a new molecular entity that is structurally related to acetaminophen. A comprehensive non-clinical safety program was conducted to support first-in-human and clinical efficacy studies based on preclinical data suggesting that the compound has comparable or enhanced antinociceptive and antipyretic efficacy without causing hepatotoxicity at supratherapeutic doses. No hepatic toxicity was noted in a mouse model sensitive to acetaminophen hepatotoxicity or in rats, dogs, and non-human primates in 28-day repeat dose toxicity studies at and above doses/exposures at which acetaminophen is known to cause hepatotoxicity. In the 28-day toxicity studies, all treatment-related findings were monitorable and reversible. Methemoglobinemia, which was observed in dogs and to a lesser extent in rats, is also observed with acetaminophen. This finding is considered not relevant to humans due to species differences in metabolism. Thyroid hypertrophy and hyperplasia were also observed in dogs and were shown to be a consequence of a species-specific UGT induction also demonstrated with increased thyroid hormone metabolism. Indirect bilirubin elevation was observed in rats as a result of UGT1A1 Inhibition. JNJ-10450232 (NTM-006) had no toxicologically relevant findings in safety pharmacology or genotoxicity studies. Together, these data supported progressing into safety and efficacy studies in humans.

Oxfendazole is a potent veterinary antiparasitic drug undergoing development for human use to treat multiple parasitic infections. Results from two recently completed phase I clinical trials conducted in healthy adults showed that the pharmacokinetics of oxfendazole is nonlinear, affected by food, and, after the administration of repeated doses, appeared to mildly affect hemoglobin concentrations. To facilitate oxfendazole dose optimization for its use in patient populations, the relationship among oxfendazole dose, pharmacokinetics, and hemoglobin concentration was quantitatively characterized using population pharmacokinetic-pharmacodynamic modeling. In fasting subjects, oxfendazole pharmacokinetics was well described by a one-compartment model with first-order absorption and elimination. The change in oxfendazole pharmacokinetics when administered following a fatty meal was captured by an absorption model with one transit compartment and increased bioavailability. The effect of oxfendazole exposure on hemoglobin concentration in healthy adults was characterized by a life span indirect response model in which oxfendazole has positive but minor inhibitory effect on red blood cell synthesis. Further simulation indicated that oxfendazole has a low risk of posing a safety concern regarding hemoglobin concentration, even at a high oxfendazole dose of 60 mg/kg of body weight once daily. The final model was further used to perform comprehensive target attainment simulations for whipworm infection and filariasis at various dose regimens and target attainment criteria. The results of our modeling work, when adopted appropriately, have the potential to greatly facilitate oxfendazole dose regimen optimization in patient populations with different types of parasitic infections.

Neurocysticercosis and trichuriasis are difficult-to-treat parasitic infections that affect more than 1.5 billion people worldwide. Oxfendazole, a potent broad-spectrum benzimidazole anthelmintic approved for use in veterinary medicine, has shown substantial antiparasitic activity against neurocysticercosis and intestinal helminths in preclinical studies. As part of a program to transition oxfendazole from veterinary medicine to human use, phase I multiple ascending dose and food effect studies were conducted. Thirty-six healthy adults were enrolled in an open-label study which evaluated (i) the pharmacokinetics and safety of oxfendazole following multiple ascending doses of oxfendazole oral suspension at 3, 7.5, and 15 mg/kg once daily for 5 days and (ii) the effect of food on oxfendazole pharmacokinetics and safety after a single 3-mg/kg dose administered following an overnight fast or the consumption of a fatty breakfast. Following multiple oral dose administration, the intestinal absorption of oxfendazole was rapid, with the time to maximum concentration of drug in serum (T-max) ranging from 1.92 to 2.56 h. A similar half-life of oxfendazole (9.21 to 11.8 h) was observed across all dose groups evaluated, and oxfendazole exhibited significantly less than a dose-proportional increase in exposure. Oxfendazole plasma exposures were higher in female subjects than in male subjects. Following daily administration, oxfendazole reached a steady state in plasma on study day 3, with minimal accumulation. Food delayed the oxfendazole Tmax by a median of 6.88 h and resulted in a 49.2% increase in the maximum observed drug concentration in plasma (C-max) and an 86.4% increase in the area under the concentration-time curve (AUC). Oxfendazole was well tolerated in all study groups, and there were no major safety signals identified in this study.

INTRODUCTION:Oxfendazole (methyl [5-(phenylsulphinyl)-1H benzimidazole-2-yl] carbamate) has a particularly long metabolic half-life in ruminants, and its metabolite fenbendazole also has anthelminthic action. A very limited number of drugs are available for the treatment of some zoonotic helminth infections, such as neurocysticercosis and echinococcosis. More recent work has expanded oxfendazole's nonclinical safety profile and demonstrated its safety and bioavailability in healthy human volunteers, thus advancing the possibility of a new and greatly needed option for antiparasitic treatment of geohelminths and tissue parasites. Areas covered: The present article reviews evidence supporting the safety and efficacy of oxfendazole against both gut and tissue dwelling helminths in animals, as well as more recent safety and pharmacokinetic data supporting its potential for use in human parasitoses. Expert commentary: The pharmacokinetics, safety, and wide spectrum of efficacy of oxfendazole are consistently demonstrated in intestinal helminth infections of animals as well as in tissue dwelling larval cestode and trematode infections in diverse animal species. Now supported by first-in-human safety and pharmacokinetic data, oxfendazole becomes a promising alternative to the limited portfolio of antiparasitic drugs available to treat helminthic diseases of humans.

Cysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS), and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of Taenia solium and has potential to be developed as an effective therapy for neurocysticercosis.

A 2-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.

Classically, G protein-coupled receptor activation by a ligand has been viewed as producing a defined response such as activation of a G protein, activation or inhibition of adenylyl cyclase, or stimulation of phospholipase C and/or alteration in calcium flux. Newer concepts of ligand-directed signaling recognize that different ligands, ostensibly acting at the same receptors, may induce different downstream effects, complicating the selection of a screening assay. Dynamic mass redistribution (DMR), a label-free technology that uses light to measure ligand-induced changes in the mass of cells proximate to the biosensor, provides an integrated cellular response comprising multiple pathways and cellular events. Using DMR, signals induced by opioid or cannabinoid agonists in cells transfected with these receptors were blocked by pharmacologically appropriate receptor antagonists as well as by pertussis toxin. Differences among compounds in relative potencies at DMR versus ligand-stimulated GTP gamma S or receptor binding endpoints, suggesting functional selectivity, were observed. Preliminary evidence indicates that inhibitors of intermediate steps in the cell signaling cascade, such as receptor recycling inhibitors, mitogen-activated protein kinase kinase/p38 mitogen-activated protein kinase inhibitors, or cytoskeletal disruptors, altered or attenuated the cannabinoid-induced response. Notable is the finding that mitogen-activated protein kinase kinase 1/2 inhibitors attenuated signaling induced by the cannabinoid type 2 receptor inverse agonist AM630 but not that stimulated by the agonist CP 55,940. Thus, DMR has the potential to not only identify ligands that activate a given G protein-coupled receptor, but also ascertain the signaling pathways engaged by a specific ligand, making DMR a useful tool in the identification of biased ligands, which may ultimately exhibit improved therapeutic profiles.

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.

Discovered as part of an effort to identify delta opioid (DOPr or DOR) agonist analgesics, JNJ-20788560 and JNJ-39204880 exhibited high DOR affinity, with Ki values of 1.7 and 2.0nM, respectively, and were selective for DOR over the mu opioid receptor (MOPr or MOR), with 596- and 122-fold selectivity, respectively. Both compounds stimulated DOR but not MOR induced GTPγS binding and were effective antihyperalgesic agents in the complete Freund's adjuvant model of thermal hyperalgesia in the rat, with oral ED50 values of 13.5 and 35mg/kg, corresponding to plasma levels of 1 and 9µM, respectively. Autoradiographic analysis of DOR and MOR occupancy in sections of brain (striatum) and lumbar spinal cord (L4–L6) was determined ex vivo, using radiolabeled naltrindole or DAMGO. Quantitative image analysis resulted in striatal DOR ED50 values of 6.9 and 10.7mg/kg, for JNJ-20788560 and JNJ-39204880 respectively, and spinal cord values of 6.4 and 3.2mg/kg, respectively. Neither compound dose-dependently occupied MOR within the dose range studied. Thus, this study confirmed the DOR selectively over MOR of both compounds following their oral administration, and further demonstrated dose-dependent DOR occupancy by each compound across its antihyperalgesic dose range. Importantly, these in vitro, in vivo, and ex vivo data revealed that the greater in vitro potency of JNJ-20788560 was paralleled by its greater in vivo potency, although JNJ-39204880 achieved higher plasma levels following its oral administration. The receptor occupancy levels observed at the pharmacologic ED50 doses of these compounds suggest the need for greater target engagement by JNJ-39204880 than by JNJ-20788560 to elicit a similar therapeutic response.

Mu-opioid analgesics are a mainstay in the treatment of acute and chronic pain of multiple origins, but their side effects, such as constipation, respiratory depression, and abuse liability, adversely affect patients. The recent demonstration of the up-regulation and membrane targeting of the delta-opioid receptor (DOR) following inflammation and the consequent enhanced therapeutic effect of delta-opioid agonists have enlivened the search for delta-opioid analgesic agents. JNJ-20788560 [9-(8-azabicyclo-[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide] had an affinity of 2.0 nM for DOR (rat brain cortex binding assay) and a naltrindole sensitive DOR potency of 5.6 nM (5'-O-(3-[(35)S]thio)triphosphate assay). The compound had a potency of 7.6 mg/kg p.o. in a rat zymosan radiant heat test and of 13.5 mg/kg p.o. in a rat Complete Freund's adjuvant RH test but was virtually inactive in an uninflamed radiant heat test. In limited studies, tolerance was not observed to the antihyperalgesic or antinociceptive effects of the compound. Unlike ibuprofen, JNJ-20788560 did not produce gastrointestinal (GI) erosion. Although morphine reduced GI motility at all doses tested and reached nearly full effect at the highest dose, JNJ-20788560 did not retard transit at the lowest dose and reached only 11% reduction at the highest dose administered. Unlike morphine, JNJ-20788560 did not exhibit respiratory depression (blood gas analysis), and no withdrawal signs were precipitated by the administration of opioid (mu or delta) antagonists. Coupled with the previously published lack of self-administration behavior of the compound by alfentanil-trained primates, these findings strongly recommend delta-opioid agonists such as JNJ-20788560 for the relief of inflammatory hyperalgesia.

High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1.

We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.

Neuropathic pain results from injury or dysfunction of the central or peripheral nervous system. The treatment of neuropathic pain is challenging, in part because of its multiple etiologies. The present study explores combinations of the analgesic tramadol and each of four anticonvulsants in the treatment of surgically induced (ligation of the L5 spinal nerve) allodynia in rats. Each of the five drugs studied exhibited a dose-dependent antiallodynic effect. When studied in combination, tramadol and each of two of the anticonvulsants (topiramate and RWJ-333369) interacted synergistically at all three ratios studied, whereas tramadol and each of the other two anticonvulsants (gabapentin and lamotrigine) exhibited a synergistic antiallodynic effect at only one of three ratios investigated. In addition, tramadol and topiramate were found to interact synergistically in a nociceptive pain model, the mouse hot-plate test. These studies suggest the benefit of using combinations of analgesics and anticonvulsants in the relief of neuropathic pain.