EX-597

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]

EX-597

Clinical data
Other names	URB597; URB-597; KDS-4103; ORG-231295
Identifiers
IUPAC name [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate
CAS Number	546141-08-6 Y
PubChem CID	1383884
IUPHAR/BPS	4339
ChemSpider	1156960 Y
UNII	PX47LB88FO
ChEBI	CHEBI:188061
ChEMBL	ChEMBL184238 Y
CompTox Dashboard (EPA)	DTXSID70203046
ECHA InfoCard	100.164.994
Chemical and physical data
Formula	C20H22N2O3
Molar mass	338.407 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1CCC(CC1)NC(=O)OC2=CC=CC(=C2)C3=CC(=CC=C3)C(=O)N
InChI InChI=1S/C20H22N2O3/c21-19(23)16-8-4-6-14(12-16)15-7-5-11-18(13-15)25-20(24)22-17-9-2-1-3-10-17/h4-8,11-13,17H,1-3,9-10H2,(H2,21,23)(H,22,24) Y Key:ROFVXGGUISEHAM-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

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

• 4-Nonylphenylboronic acid
• LY-2183240
• PF-04457845

References

1. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, et al. (2006). "Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597)". CNS Drug Reviews. 12 (1): 21–38. doi:10.1111/j.1527-3458.2006.00021.x. PMC 6741741. PMID 16834756.
2. "EX 597". AdisInsight. Springer Nature Switzerland AG. 28 November 2023. Retrieved 6 August 2024.
3. Mor M, Rivara S, Lodola A, Plazzi PV, Tarzia G, Duranti A, et al. (October 2004). "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. doi:10.1021/jm031140x. PMID 15456244. S2CID 43473180.
4. Alexander JP, Cravatt BF (November 2005). "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. doi:10.1016/j.chembiol.2005.08.011. PMC 1994809. PMID 16298297.
5. Russo R, Loverme J, La Rana G, Compton TR, Parrott J, Duranti A, et al. (July 2007). "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. doi:10.1124/jpet.107.119941. PMID 17412883. S2CID 40603248.
6. Bambico FR, Duranti A, Nobrega JN, Gobbi G (March 2016). "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. doi:10.1016/j.euroneuro.2015.12.027. hdl:11576/2631931. PMID 26747370. S2CID 45109526.
7. Solinas M, Chauvet C, Lafay-Chebassier C, Jaafari N, Thiriet N (February 2021). "Environmental enrichment-inspired pharmacological tools for the treatment of addiction". Current Opinion in Pharmacology. 56: 22–28. doi:10.1016/j.coph.2020.09.001. PMID 32966941. S2CID 221888359.
8. Chauvet C, Nicolas C, Thiriet N, Lardeux MV, Duranti A, Solinas M (December 2014). "Chronic stimulation of the tone of endogenous anandamide reduces cue- and stress-induced relapse in rats". The International Journal of Neuropsychopharmacology. 18 (1): pyu025. doi:10.1093/ijnp/pyu025. PMC 4368869. PMID 25522382.
9. "Kadmus Pharmaceuticals". Archived from the original on 19 December 2005.

Further reading

• Kathuria S, Gaetani S, Fegley D, Valiño F, Duranti A, Tontini A, et al. (January 2003). "Modulation of anxiety through blockade of anandamide hydrolysis". Nature Medicine. 9 (1): 76–81. doi:10.1038/nm803. PMID 12461523.