Delving into the Latest Updates on URB937 with Synapse

Exposure to traumatic events can lead to alterations in social and anxiety-related behaviors. Emerging evidence suggests that peripheral host-defense processes are implicated in the expression of stress-induced behavioral responses and may be targeted to mitigate the negative sequalae of stress exposure.

Objectives:

In this study, we used the peripherally restricted FAAH inhibitor URB937 to investigate the effects of the fatty acyl ethanolamide (FAE) family of lipid mediators – which include the endocannabinoid anandamide and the endogenous PPAR-α agonists, oleoylethanolamide and palmitoylethanolamide – on behavioral and peripheral biochemical responses to two ethologically distinct rat models of stress.

Methods:

Male adult rats were exposed to acute social defeat, a model of psychological stress (Experiment 1), or to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a test of innate predator-evoked fear (Experiment 2), and subsequently treated with URB937 (1 or 3 mg/kg, intraperitoneal) or vehicle. Behavioral analyses were conducted 24 h (Experiment 1) or 7 days (Experiment 2) after exposure.

Results:

URB937 administration prevented the emergence of both social avoidance behavior after social defeat stress and anxiety-related behaviors after TMT exposure. Further, URB937 administration blocked social defeat-induced transient increase in plasma concentrations of pro-inflammatory cytokines and the elevation in plasma corticosterone levels observed 24 h after social defeat

Conclusions:

Enhancement of peripheral FAAH-regulated lipid signaling prevents the emergence of stress-induced social avoidance and anxiety-like behaviors in male rats through mechanisms that may involve an attenuation of peripheral cytokine release induced by stress exposure.

01 Nov 2022·Experimental neurology

Synergistic antinociceptive effects of concomitant NAAA and peripheral FAAH inhibition

Article

Author: Piomelli, Daniele ; Fotio, Yannick ; Mabou Tagne, Alex ; Uppal, Parwinder Singh

The intracellular lipid amidases, fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA), terminate the actions of anandamide and palmitoylethanolamide (PEA), two antinociceptive and anti-inflammatory lipid-derived mediators. Here we show, confirming prior research, that small-molecule inhibitors of peripheral FAAH (compound URB937) and systemic NAAA (compound ARN19702) individually attenuate, in male CD-1 mice, pain-related behaviors and paw inflammation in the formalin and carrageenan tests. More importantly, isobolographic analyses revealed that the combination of URB937 and ARN19702 produced substantial synergistic (greater than additive) antinociceptive effects in both models as well as additive anti-inflammatory effects in the carrageenan test. Together, the findings uncover a functional interplay between FAAH and NAAA substrates in the control of nociception, which might be exploited clinically to develop safe and effective pain management strategies.

01 Jul 2020·British Journal of Pharmacology

Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice

Article

Author: Piomelli, Daniele ; Fotio, Yannick ; Ahmed, Faizy ; Guaman Tipan, Pablo ; Palese, Francesca

Background and Purpose:

Fatty acid amide hydrolase (FAAH) is an intracellular serine amidase that terminates the signalling of various lipid messengers involved in pain regulation, including anandamide and palmitoylethanolamide. Here, we investigated the effects of pharmacological or genetic FAAH removal on tolerance to the anti‐nociceptive effects of morphine.

Experimental Approach:

We induced tolerance in male and female mice by administering twice‐daily morphine for 7 days while monitoring nociceptive thresholds by the tail immersion test. The globally active FAAH inhibitor URB597 (1 and 3 mg·kg−1, i.p.) or the peripherally restricted FAAH inhibitor URB937 (3 mg·kg−1, i.p.) were administered daily 30 min prior to morphine, alone or in combination with the cannabinoid CB1 receptor antagonist AM251 (3 mg·kg−1, i.p.), the CB2 receptor antagonist AM630 (3 mg·kg−1, i.p.), or the PPAR‐α antagonist GW6471 (4 mg·kg−1, i.p.). Spinal levels of FAAH‐regulated lipids were quantified by LC/MS‐MS. Gene transcription was assessed by RT‐qPCR.

Key Results:

URB597 prevented and reversed morphine tolerance in both male and female mice. This effect was mimicked by genetic FAAH deletion, but not by URB937. Treatment with AM630 suppressed, whereas treatment with AM251 or GW6471, attenuated the effects of URB597. Anandamide mobilization was enhanced in the spinal cord of morphine‐tolerant mice. mRNA levels of the anandamide‐producing enzyme N‐acyl‐phosphatidylethanolamine PLD (NAPE‐PLD) and the palmitoylethanolamide receptor PPAR‐α, but not those for CB2 , CB1 receptors or FAAH, were elevated in spinal cord

Conclusion and Implications:

FAAH‐regulated lipid signalling in the CNS modulated opiate tolerance, suggesting FAAH as a potential target for opiate‐sparing medications.

1

News (Medical) associated with URB937

10 Jul 2023

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Exxel Pharma to Participate in the Virtual Investor Summer Spotlight Series

Live moderated video webcast with members of the Exxel Pharma Leadership Team on Tuesday, July 11th 1:00 PM ET AURORA, CO / ACCESSWIRE / July 10, 2023 / Exxel Pharma ("Exxel" or the "Company"), an early-stage pharma company working to develop URB937 as a safe and effective treatment for patients suffering from chronic cough, today announced that Soren Mogelsvang, PhD, President and Chief Executive Officer and Daniele Piomelli, PhD, MD (h.c.), Chief Scientific Officer of Exxel, will participate in the Virtual Investor Summer Spotlight Series on Tuesday, July 11, 2023 at 1:00 PM ET. The virtual event will include a brief overview of the Company's business, a moderated roundtable discussion and an interactive Q&A session. A live video webcast of the event will be available on the Investors page of the Company's website (exxelpharma.com). A webcast replay will be available two hours following the live event and will be accessible for 90 days. About Exxel Pharma Exxel Pharma is an early-stage pharma company working to develop URB937 as a safe and effective treatment for patients suffering from chronic cough. URB937 is a highly potent and selective FAAH (fatty acid amide hydrolase) inhibitor, which exhibits remarkable safety by being entirely excluded from the CNS. The compound was licensed from the University of California and is supported by more than 20 scientific publications. A comprehensive series of IND-enabling studies and a pre-IND meeting have been completed for URB937, the Company expects to begin clinical testing in 2024. For more information, please visit exxelpharma.com. Investor Contact Jenene Thomas Chief Executive Officer JTC Team, LLC T: 833.475.8247 exxel@jtcir.com SOURCE: Exxel Pharma, Inc. View source version on accesswire.com:

100 Deals associated with URB937

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Indication	Highest Phase	Country/Location	Organization	Date
Urinary Bladder, Overactive	Preclinical	Germany	Deutsche Forschungsgemeinschaft	01 Apr 2014
Pain	Preclinical	United States	University of California, Irvine	19 Sep 2010