69 - Summary of the Preclinical Pharmacology of NTM-006 (formerly JNJ-10450232): A Novel Orally-Active Non-Opioid Analgesic
Robert Raffa1,2,3, Joseph Pergolizzi4,5, John Carson6, Ellen Codd7,8, James McNally9
1Neumentum, Tucson, AZ, USA. 2Univ. of AZ, Tucson, AZ, USA. 3Temple Univ., Philadelphia, PA, USA. 4Neumentum, Naples, FL, USA. 5NEMA, Naples, FL, USA. 6CaRafe Drug Innovation, Princeton, NJ, USA. 7Codd Consulting, Blue Bell, PA, USA. 8Oxfendazole Develop Group, Blue Bell, PA, USA. 9Abzena, Bristol, PA, USA
Purpose JNJ-10450232, a structural analog of acetaminophen, was designed to retain the good analgesic efficacy, but not have the usual liabilities, associated with opioid and other classes of analgesics (i.e., gastrointestinal, cardiovascular, respiratory and hepatic safety – or the abuse potential). Its clinical analgesic efficacy was demonstrated recently in a dental pain model, and its full potential in terms of efficacy and possible therapeutic use in chronic/neuropathic pain continues in development as NTM-006. We summarize here its basic preclinical pharmacology. Methods JNJ-10450232was screened in standard in vitro radioligand binding assays and in in vivo animal models of acute pain, thermal hyperalgesia induced by an intraplantar injection of either carrageenan or Complete Freund’s Adjuvant, a postsurgical model with tactile allodynia, and it was tested for antipyresis. In vivo safety pharmacology studies were conducted in several species and in in vitro assays for toxicity. Results JNJ-10450232 had no significant affinity at more than four-dozen receptor types and subtypes (including opioid MOP, DOP, KOP; CB1 and CB2); enzymes (e.g., kinases and COX-1 and COX-2), or neurotransmitter reuptake site (norepinephrine). It did display concentration-related effect on binding at adenosine A3 receptors (A3R). It demonstrated antinociceptive, anti-hyperalgesic, and antipyretic activity in animal models suggestive of clinical efficacy in acute and possibly chronic/neuropathic pain conditions. Conclusions JNJ-10450232 demonstrated oral non-opioid, non-NSAID antinociceptive and antipyretic activity in several animal models predictive of analgesic efficacy against acute and chronic pain. Although structurally similar to APAP, it was different with respect to toxicology (little or no hepatotoxicity, as designed), metabolism (Phase-II), pharmacokinetics (much longer duration), as well as its overall in vitro and in vivo pharmacology profile. Based on in vitro assay screens, the compound is non-opioid, non-cannabinoid and non-NSAID (does not inhibit COX-1 or -2 cyclooxygenase isozymes) at doses that produce its antinociceptive and antipyretic effects. This preclinical pharmacologic profile is consistent with its efficacy and safety demonstrated in clinical testing. Future work as NTM-006 is aimed at elucidation of its full efficacy potential and possible use for chronic/neuropathic pain conditions with/without an inflammatory component.