Biased potent opioid-like agonists as improved medications to treat chronic and acute pain and methods of using the same
Inventors
Rice, Kenner Cralle • Jacobson, Arthur E. • Li, Fuying • GUTMAN, Eugene S. • Bow, Eric W.
Assignees
US Department of Health and Human Services
Publication Number
US-11352365-B2
Publication Date
2022-06-07
Expiration Date
2039-03-18
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Abstract
The present invention is directed to a compound having Formula (I) and its enantiomer: wherein the definitions of n, R, X, Y and Y3, and Z are provided in the disclosure. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use as opioid-like agonists in the treatment of pain.
Core Innovation
The present invention is directed to compounds having Formula (I) and their enantiomers, specifically conformationally constrained 4-aryl-piperidine compounds. These compounds are opioid-like agonists designed for the treatment of pain. The invention also encompasses pharmaceutical compositions containing these compounds and methods of their use as opioid receptor agonists.
The problem addressed by the invention arises from the known side effects of classical opioid analgesics, such as morphine, which activate both G-protein and beta-arrestin pathways at opioid receptors. Activation of G-protein pathways mediates analgesia, while beta-arrestin pathways are linked to adverse effects including respiratory depression, constipation, tolerance, and dependence. There is a need for efficacious analgesics that retain desired effects while minimizing these side effects. Current compounds like TRV-130 (Oliceridine) and PZM-21 are limited in availability and efficacy.
The invention provides compounds that are biased potent opioid-like agonists favoring G-protein pathway activation without recruiting beta-arrestin. These compounds bind to opioid receptors with high potency and selectivity, enhancing analgesic effects while reducing undesirable side effects associated with classic opioids. The disclosed compounds also encompass various pharmaceutical compositions and methods of treatment, including use alone or in combination with other opioids or active agents.
Claims Coverage
The patent includes one independent claim directly directed to the compound of Formula (I) or its enantiomer, another independent claim directed to pharmaceutical compositions containing the compound, and a further independent claim directed to methods of prevention or treatment of pain using the compound.
Compound having Formula (I) or its enantiomer
A compound characterized by Formula (I) or its enantiomer with defined substituents including X, Y1, Y2, Y3, Z, R, and n as specified. The compound has conformationally constrained 4-aryl-piperidine structures with various substitutions and chemical functionalities.
Pharmaceutical composition comprising the compound
A pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (I) or its enantiomer together with a pharmaceutically acceptable carrier, which may include binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, wetting agents, and optionally additional active agents including opioids.
Method of prevention or treatment of pain
A method of preventing or treating pain by administering to a patient a therapeutically effective amount of the compound of Formula (I) or its enantiomer, optionally combined with one or more additional active ingredients, including opioids selected from alfentanil, buprenorphine, butorphanol, codeine, and others.
The independent claims cover the novel opioid-like compounds with specified structures and substitutions, their inclusion in pharmaceutical compositions with carriers and optional additional drugs, and their use in methods for preventing or treating pain, including pain associated with gastrointestinal dysfunction or post-operative opioid-induced conditions.
Stated Advantages
The compounds act as full agonists at mu-opioid receptors but do not recruit beta-arrestin, potentially reducing undesirable side effects such as respiratory depression, constipation, tolerance, and dependence.
The compounds exhibit potent analgesic effects with bias towards G-protein activation over beta-arrestin signaling, offering improved efficacy and safety compared to classical opioids.
Certain compounds show unique receptor profiles such as kappa receptor antagonism and low delta/mu potency ratios, which may contribute to reduced respiratory depression without loss of analgesia.
Documented Applications
Use as opioid-like agonists in pharmaceutical compositions for the treatment of acute and chronic pain in humans and non-human animals.
Treatment of pain associated with gastrointestinal dysfunction including irritable bowel syndrome, opioid-bowel dysfunction, colitis, opioid-induced emesis, decreased gastric motility, inhibition of intestinal propulsion, and constipation.
Treatment of post-operative or opioid-induced ileus.
Use in combination therapy with other opioids such as alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, morphine, oxycodone, and tramadol.
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