A mainstay of the analgesic pharmacopeia for nearly seven decades and alone in its class, acetaminophen relieves mild-to-moderate pain and fever, without similar adverse gastrointestinal and cardiovascular effects associated with non-steroidal anti-inflammatory drugs. While safe and effective when used as directed, acetaminophen overdose may produce liver injury. This report describes discovery and pharmacological characterization of JNJ-10450232/NTM-006, an acetaminophen structural analog designed to retain the efficacy and overall safety profile of acetaminophen without risk of hepatotoxicity following overdose. In the carrageenan and complete Freund's adjuvant models of inflammatory pain and yeast model of fever in rats, JNJ-10450232/NTM-006 exhibited statistically significant effects comparable to acetaminophen in both maximal efficacy and potency. In rat pharmacokinetic studies, JNJ-10450232/NTM-006 exhibited a comparable maximal plasma concentration but higher volume of distribution and longer half-life than acetaminophen, potentially conferring an extended duration of action. In a mouse model of liver injury, acetaminophen produced elevations in aspartate and alanine transaminase activities and signs of hepatic necrosis, whereas JNJ-10450232/NTM-006 did not. Finally, following systemic administration, JNJ-10450232/NTM-006 and acetaminophen produced comparable peripheral levels of para-aminophenol and brain levels of pharmacologically active metabolite N-arachidonoyl-phenolamine (AM404), consistent with the hypothesis that both parent molecules are prodrugs and share the same central mechanism of analgesic action. Taken together, these results suggest JNJ-10450232/NTM-006 as a potentially clinically useful analgesic/antipyretic with improved benefit-to-risk ratio compared with current standards of care.

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.

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.

HISTORY: 21 year old college softball player who presented with a 6 month history of amenorrhea thought to be due to overtraining and or birth control pill she had been taking in the interim. PHYSICAL EXAMINATION: GEN. NAD. HEENT- WNL. Heart- RRR no GMR. Lungs- CTAB. Abdomen- positive bowel sounds x 4. Extremities- No edema. DIFFERENTIAL DIAGNOSIS: Pregnancy, Overtraining, Birth control pillls, PCOS, Thyroid disease, Prolactinoma, Ovarian failure, endometrial failure TEST AND RESULTS: Urine pregnancy- Negative, TSH-Normal, Prolactin-115.2, MRI Brain- 3mm X 3mm Microadenoma of pituitary gland. FINAL WORKING DIAGNOSIS: Secondary Amenorrhea due to Prolactinoma TREATMENT AND OUTCOMES: Patient was started on weekly Dostinex Therapy. She is tolerating therapy well.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The synthesis and structure-activity relationships of a novel series of aroylpyrrole alkylamides as potent selective bradykinin B(2) receptor antagonists are described. Several members of this series display nanomolar affinity at the B(2) receptor and show activity in an animal model of antinociception.