Peripherally-restricted dual-acting kappa and delta opioid agonist for analgesia in pain states involving the inflammatory response

a dual-acting, opioid agonist technology, applied in the direction of nervous disorders, drug compositions, organic chemistry, etc., can solve the problems of prescription opioids being highly addictive, unwanted side effects, and being widely misused, so as to enhance the kappa effect and reduce urinary output

Inactive Publication Date: 2022-09-15
CAVENTURE DRUG DISCOVERY INC
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

Compound 1 achieves effective pain relief comparable to central-nervous system-acting opioids like morphine without addiction or other CNS side effects, offering improved analgesia and reduced urinary output compared to kappa agonists.

Problems solved by technology

However, because these drugs can cross the blood-brain barrier to the central nervous system, their use can cause unwanted side effects such as addiction.
Moreover, because not all pain is mediated by MORs, these drugs may also be only partially effective for the treatment of certain types of pain.
Specifically, prescription opioids can be highly addictive and are widely misused.
Despite their widespread use, many prescription opioids are poorly effective for certain types of pain such as inflammatory and / or chronic pain.
Moreover, in bone cancer, multiple other non-opioid pain pathways are active, including involvement of inflammatory mediators of bradykinin, further limiting the effectiveness of treatments that only target MOR (Mantyh, P. Bone cancer pain: causes, consequences, and therapeutic opportunities.
The reduced activity of MOR in these and other types of pain can thus reduce the effectiveness of drugs such as traditional opioids that only target MOR (e.g., morphine).
Thus, in some cases patients suffering from chronic pain may realize incomplete relief when using traditional opioids such as morphine, even despite increasing doses.
This cycle of increasing dosage without adequate pain relief can result in dependence and addiction.
On the other hand, due to concerns over addiction and overdose, others who experience chronic pain may suffer undertreatment (Reville et al.
For instance, in many parts of the developing world, access to opioids even for acute pain and / or cancer pain can be restricted due to concerns over addiction and overdose outlined above (Id).
Even in the United States, some patients can suffer from an undertreatment of pain.
For example, patients with cognitive impairment and the elderly can be especially susceptible to the central nervous system effects of traditional opioids such as morphine and in some cases are not prescribed enough to meet their pain management needs (American Geriatrics Panel on the Pharmacological Management of Persistent Pain in Older Persons.
Furthermore, alternative effective analgesics are not available (Id).
This represents a significant unmet medical need and is a significant public health crisis that does not receive adequate attention (Id).
Despite the unmet need for safe and effective pain relievers, no such drug is currently available.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Peripherally-restricted dual-acting kappa and delta opioid agonist for analgesia in pain states involving the inflammatory response
  • Peripherally-restricted dual-acting kappa and delta opioid agonist for analgesia in pain states involving the inflammatory response
  • Peripherally-restricted dual-acting kappa and delta opioid agonist for analgesia in pain states involving the inflammatory response

Examples

Experimental program
Comparison scheme
Effect test

example 1

Model of Pain in Mice

[0120]The objective of this study was to evaluate the effects of Compound 1 and a peripherally-restricted kappa agonist (IC1204448) on formalin-evoked spontaneous nociceptive behaviors in mice. The study was performed by video recording of formalin-induced nociceptive behavior and then off-line scoring using a computer.

[0121]Subcutaneous plantar injection of formalin causes a bi-phasic nocifensive behavioral response in rodents. The early phase (phase 1) lasts for about 5-10 minutes, following which an interphase occurs without any discernible nociceptive reactions, after which the late phase (phase 2) nociceptive reaction ensues continuing from about 20-60 min following formalin injection. Thus, phase 2 of the formalin model is a model of continuously present, persistent pain, and is widely used for rapid screening of novel analgesic compounds. The model encompasses inflammatory, neurogenic and central mechanisms of nociception, and the late phase (phase 2), in...

example 2

Model of Pain in Rats

[0131]This study evaluated the efficacy of a single intraperitoneal injection of Compound 1 on hyperalgesic nociceptive behaviors in an CFA (Complete Freund's Adjuvant) Model of Rheumatoid Arthritis Pain in Rats.

[0132]Rats have been used as a reliable animal model for the study of pain due to many similarities of the peripheral and central nervous systems of rats and humans. These similarities are evident both in terms of behavioral responses to painful conditions and in terms of pain relieving effects of various therapeutic agents (i.e. opiates and nonsteroidal anti-inflammatory drugs) in both species.

Methods

Animal Selection

[0133]A statistical power calculator (Massachusetts General Hospital on-line power calculator, http: / / hedwig.mgh.harvard.edu / sample_size / size.html) was used to determine the appropriate group size to ensure interpretable and reproducible results. Data from previous studies were input into the calculator and the group size was calculated base...

example 3

ic Pain Model in Rats

[0145]This study evaluated the efficacy of a single intraperitoneal injection of Compound 1 and the comparator, gabapentin, in the spinal nerve ligation (SNL) model for neuropathic pain in the rat. Rats have been used as a reliable animal model for the study of pain due to many similarities of the peripheral and central nervous systems of rats and humans. These similarities are evident both in terms of behavioral responses to painful conditions and in terms of pain relieving effects of various therapeutic agents (i.e. opiates and nonsteroidal anti-inflammatory drugs) in both species. Further, rats are vertebrates, which is necessary when investigating the effects of neuropathic pain.

Methods

Animal Selection

[0146]A statistical power calculator (Massachusetts General Hospital on-line power calculator, http: / / hedwig.mgh.harvard.edu / sample_size / size.html) was used to determine the appropriate group size to ensure interpretable and reproducible results. Data from prev...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present disclosure teaches the use of a dual-acting opioid agonist for the treatment of pain (e.g., inflammatory pain). The opioid agonist activates both the kappa and delta opioid receptors to provide synergistic reduction in pain. The opioid agonist is peripherally restricted and does not cross the blood-brain barrier.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to, and benefit of, U.S. Provisional Patent Application No. 62 / 529,285 filed Jul. 6, 2017, the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE DISCLOSURE[0002]The present disclosure teaches the use of a dual-acting opioid agonist for the treatment of pain (e.g., inflammatory pain). The opioid activates both the kappa and delta opioid receptors to provide synergistic reduction in pain, dual agonism.BACKGROUND OF THE DISCLOSURE[0003]Opioid analgesics can be useful analgesics for the treatment of pain. These drugs, such as heroin and morphine, are agonists at mu opioid receptors (MORs) in the central nervous system. However, because these drugs can cross the blood-brain barrier to the central nervous system, their use can cause unwanted side effects such as addiction. Moreover, because not all pain is mediated by MORs, these drugs may also be only partially effective for ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/5517A61P29/00
CPCA61K31/5517A61P29/00A61K31/4188A61K31/551A61P25/04C07D491/00C07D403/14
InventorHARTRICK, CRAIG
OwnerCAVENTURE DRUG DISCOVERY INC