Compounds and Methods for Treatment of Visceral Pain

Inactive Publication Date: 2020-03-12
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present disclosure has various applications, and the detailed description provided herein is only for illustrative purposes. The technical effect of this disclosure is to provide a more efficient and effective way to perform a certain process or function. The specific examples given in this description are meant to show how the disclosure can be used in a specific situation or circumstance. However, the scope of the disclosure is not limited to these examples.

Problems solved by technology

Visceral pain can also be caused by problems with abdominal muscles and the abdominal wall, such as spasm.
They include opioids that have the potential for developing tolerance / tachyphylaxis, addiction and abuse, and potentially fatal respiratory depression; gabapentinoids that are safer than opioids but also produce adverse cognitive effects; tricyclic antidepressants that show some efficacy but can also produce somnolence, hypotension, and arrhythmias; and non-steroidal anti-inflammatories (NSAIDs; drugs such as ibuprofen and naproxen) which when administered long term may be associated with an increased risk of gastrointestinal injury / bleeding, cardiac events, hypertension, kidney injury, and death.
There is a need for alternative approaches to targeted pain management for visceral pain, especially for abdominal pain that is poorly managed in IBD due to limited specific options.

Method used

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  • Compounds and Methods for Treatment of Visceral Pain
  • Compounds and Methods for Treatment of Visceral Pain
  • Compounds and Methods for Treatment of Visceral Pain

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of Compounds

[0581]The preparation of compounds of Formulas Ia-Id, including Compound A, is described in International Patent Application No. PCT / US2010 / 002360, published as International Publication No. WO2011 / 025541, the entire contents of which are incorporated herein by reference in their entirety.

[0582]The preparation of crystal forms of Compound A, including the anhydrous, non-solvated crystalline form, is described in International Patent Application No. PCT / US2012 / 026506, published as International Publication No. WO2012 / 116276, the entire contents of which are incorporated herein by reference in their entirety.

example 2

us Time-Resolved Fluorescence (HTRF®) Assay For Direct cAMP Measurement

[0583]A: CB2 Assay

[0584]Compounds were screened for agonists and inverse agonists of CB2 receptor (e.g., human CB2 receptor) using the HTRF® assay for direct cAMP measurement (Gabriel et al., ASSAY and Drug Development Technologies, 1:291-303, 2003) in recombinant CHO-K1 cells stably transfected with the CB2 receptor. CHO-K1 cells were obtained from ATCC® (Manassas, Va.; Catalog # CCL-61). An agonist of the CB2 receptor was detected in the HTRF® assay for direct cAMP measurement as a compound which decreased cAMP concentration. An inverse agonist of the CB2 receptor was detected in the HTRF® assay for direct cAMP measurement as a compound which increased cAMP concentration. The HTRF® assay also was used to determine EC50 values for CB2 receptor agonists and inverse agonists.

[0585]B: CB1 Assay

[0586]Compounds were also screened for agonists and inverse agonists of the CB1 receptor (e.g., human CB1 receptor) using H...

example 3

r β-Arrestin Assay

[0598]A: CB2 Assay

[0599]Compounds were screened for agonists of the human CB2 receptor using the DiscoveRx PathHunter β-arrestin assay which measures the β-arrestin binding to the CB2 receptor upon its activation. CB2 was cloned into the pCMV-PK vector (DiscoveRx, Fremont, Calif.; catalog #93-0167) and transfected into the CHO-K1 EA-Arrestin parental cell line (DiscoveRx, Fremont, Calif.; catalog #93-0164). CHO-K1 positive clones stably expressing the CB2—ProLink fusion protein were identified by their responses to the CB2 agonist CP55,940. Clone #61 was chosen for its big agonist window and homogenous expression as detected by anti-HA flow cytometry.

[0600]Principle of the Assay:

[0601]The PathHunter-arrestin assay measures the interaction of β-arrestin with activated GPCRs using Enzyme Fragment Complementation (Yan et al., J. Biomol. Screen. 7: 451-459, 2002). A small, 42 amino acid β-galactosidase fragment, Prolink, is fused to the c-terminus of a GPCR, and β-arre...

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Abstract

The present invention relates to certain compounds of Formula Ia and pharmaceutical compositions thereof and their use in methods for the alleviation and / or treatment of visceral pain, for example abdominal pain; pelvic pain; male pelvic pain; pain from an internal organ; bladder pain; painful bladder syndrome; post-surgical abdominal pain (e.g., GI resection, hysterectomy, oophorectomy, C-section, and the like); or pain arising from or related to: pancreatitis (e.g., chronic pancreatitis), prostatitis (e.g., chronic prostatitis), inflammatory bowel disease (e.g., Crohn's disease), endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), epididymitis (e.g., chronic epididymitis), or post-surgical abdominal lesions. In some embodiments, the visceral pain is consequent to inflammatory bowel disease, for example Crohn's disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 62 / 503,280, filed on May 8, 2017, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to certain compounds of Formula Ia and pharmaceutical compositions thereof and their use in methods for the alleviation and / or treatment of visceral pain, for example abdominal pain; pelvic pain; pain from an internal organ; or pain arising from or related to pancreatitis (e.g., chronic pancreatitis), inflammatory bowel disease, endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), or post-surgical abdominal lesions. In some embodiments, the visceral pain arises from or is related to inflammatory bowel disease, for example Crohn's disease.BACKGROUND[0003]Visceral pain is generally the result of damage or injury to internal organs, and is one of the most common forms of pain. Visce...

Claims

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Application Information

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IPC IPC(8): A61K31/497A61P29/00
CPCA61K31/497A61P29/00A61K31/416A61K31/4439A61K31/675A61P1/00C07D403/04C07B2200/13
InventorLASSEN, CHERYL GERALDINEPICCIRILLO, MARCELO FABIAN
OwnerARENA PHARMA