Opioids like morphine and hydrocodone are generally the most effective therapeutics for treatment of moderate to severe pain. However, their use is limited by serious side effects - tolerance, constipation, respiratory depression, physical dependence and high addictive potential. The frequency of clinical pain, coupled with a lack of alternative therapeutic options has led to a national health crisis centered on prescription opioid abuse. Alternative pain relievers with the analgesic potency of conventional opioids, but devoid of narcotic side effects are an immediate need. The goal of this project is to develop and commercialize an alternative to conventional opioid analgesics with reduced side effects and without the addictive properties common to mu-opioid agonists. Our lead molecule, Blue181 is a highly selective agonist for a novel CNS target that is a potent analgesic without apparent addictive potential, tolerance, or physical dependence. We started the pre-clinical development of Blue181 using a combination of federal and private funds to scale up and develop an industrial synthetic process for generating large amounts of Blue181 and shown that Blue181 does not produce respiratory depression, reduction of GI transit, inhibition of hERG in the therapeutic range, or genetic toxicity. We also have a preliminary understanding of the pharmacokinetic profile of Blue181. We will now finish all the remaining IND-enabling studies targeting an initial indication of IV postoperative pain for Blue181. We will continue our efforts on developing an FDA-compliant process for preparation of Blue181 in the kilogram scale that would be amenable for later cGMP synthesis and prepare a CMC package for IND filing. We will also perform studies to further delineate the PK and metabolic profile of Blue181 and determine the no- observable-adverse-effects-level (NOAEL) in the toxicity species. Finally, we will finish safety pharmacology studies (pulmonary toxicity and cardiotoxicity) and GLP toxicity in two species. At the end of the project period, Blue181 will be an IND-ready asset and can be advanced into Phase 1 human trials.
Opioids such as morphine and hydrocodone are considered the most effective treatment for pain, however, they come with a number of serious side effects including addictive potential and leading to ~140 deaths every day in the US. This proposal will advance towards commercialization a novel small molecule, Blue181, which produces excellent analgesia with no narcotic side effects identified in pre-clinical models. The targeted impact of this work is eventual clinical displacement of mu-opioid agonists, which have created a national health crisis centered on their abuse liability and addictive potential.
| Yekkirala, Ajay S; Roberson, David P; Bean, Bruce P et al. (2017) Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov 16:545-564 |
| Knezevic, Nebojsa Nick; Yekkirala, Ajay; Yaksh, Tony L (2017) Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics. Anesth Analg 125:1714-1732 |
