Chemistry:EX-597

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EX-597 (former developmental code names URB-597, KDS-4103, and ORG-231295) is a fatty acid amide hydrolase inhibitor (FAAH inhibitor)[1] which is under development for the treatment of social anxiety disorder (or social phobia) and post-traumatic stress disorder (PTSD).[2]

It is a relatively selective and irreversible inhibitor of the enzyme fatty acid amide hydrolase (FAAH).[3][4] FAAH is the primary degradatory enzyme for the endocannabinoid anandamide and, as such, inhibition of FAAH leads to an accumulation of anandamide in the CNS and periphery where it activates cannabinoid receptors. EX-597 has been found to elevate anandamide levels and have activity against neuropathic pain in a mouse model.[5]

Preclinical studies have shown FAAH inhibitors to increase brain-derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex,[6] highlighting their potential in addiction treatment as "enviromimetics".[7] Indeed, Chauvet et al. found that chronic EX-597 administration in rats "significantly reduces cocaine-seeking behaviour and cue- and stress-induced relapse".[8]

EX-597 was at one point being developed by Kadmus Pharmaceuticals, Inc. for clinical trials in humans.[9]

See also

References

  1. ↑ "Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597)". CNS Drug Reviews 12 (1): 21–38. 2006. doi:10.1111/j.1527-3458.2006.00021.x. PMID 16834756. 
  2. ↑ "EX 597". AdisInsight. Springer Nature Switzerland AG. 28 November 2023. https://adisinsight.springer.com/drugs/800022923. 
  3. ↑ "Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies". Journal of Medicinal Chemistry 47 (21): 4998–5008. October 2004. doi:10.1021/jm031140x. PMID 15456244. 
  4. ↑ "Mechanism of carbamate inactivation of FAAH: implications for the design of covalent inhibitors and in vivo functional probes for enzymes". Chemistry & Biology 12 (11): 1179–1187. November 2005. doi:10.1016/j.chembiol.2005.08.011. PMID 16298297. 
  5. ↑ "The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice". The Journal of Pharmacology and Experimental Therapeutics 322 (1): 236–242. July 2007. doi:10.1124/jpet.107.119941. PMID 17412883. 
  6. ↑ "The fatty acid amide hydrolase inhibitor URB597 modulates serotonin-dependent emotional behaviour, and serotonin1A and serotonin2A/C activity in the hippocampus". European Neuropsychopharmacology 26 (3): 578–590. March 2016. doi:10.1016/j.euroneuro.2015.12.027. PMID 26747370. 
  7. ↑ "Environmental enrichment-inspired pharmacological tools for the treatment of addiction". Current Opinion in Pharmacology 56: 22–28. February 2021. doi:10.1016/j.coph.2020.09.001. PMID 32966941. 
  8. ↑ "Chronic stimulation of the tone of endogenous anandamide reduces cue- and stress-induced relapse in rats". The International Journal of Neuropsychopharmacology 18 (1). December 2014. doi:10.1093/ijnp/pyu025. PMID 25522382. 
  9. ↑ "Kadmus Pharmaceuticals". http://www.kadmuspharma.com/. 

Further reading

  • "Modulation of anxiety through blockade of anandamide hydrolysis". Nature Medicine 9 (1): 76–81. January 2003. doi:10.1038/nm803. PMID 12461523. 



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