EX-597 explained

Verifiedrevid:470619330
Verifiedfields:changed
Watchedfields:changed
Cas Number:546141-08-6
Pubchem:1383884
Iuphar Ligand:4339
Chemspiderid:1156960
Unii:PX47LB88FO
Chebi:188061
Chembl:184238
Synonyms:URB597; URB-597; KDS-4103; ORG-231295
Iupac Name:[3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate
C:20
H:22
N:2
O:3
Smiles:C1CCC(CC1)NC(=O)OC2=CC=CC(=C2)C3=CC(=CC=C3)C(=O)N
Stdinchi: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)
Stdinchikey:ROFVXGGUISEHAM-UHFFFAOYSA-N

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

Further reading

Notes and References

  1. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP, Parrott JA, Putman D . Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597) . CNS Drug Reviews . 12 . 1 . 21–38 . 2006 . 16834756 . 6741741 . 10.1111/j.1527-3458.2006.00021.x .
  2. Web site: EX 597 . AdisInsight . Springer Nature Switzerland AG . 28 November 2023 . 6 August 2024.
  3. Mor M, Rivara S, Lodola A, Plazzi PV, Tarzia G, Duranti A, Tontini A, Piersanti G, Kathuria S, Piomelli D . 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 . 15456244 . 10.1021/jm031140x . 43473180 .
  4. Alexander JP, Cravatt BF . 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 . 16298297 . 1994809 . 10.1016/j.chembiol.2005.08.011 .
  5. Russo R, Loverme J, La Rana G, Compton TR, Parrott J, Duranti A, Tontini A, Mor M, Tarzia G, Calignano A, Piomelli D . 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 . 17412883 . 10.1124/jpet.107.119941 . 40603248 .
  6. Bambico FR, Duranti A, Nobrega JN, Gobbi G . 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 . 26747370 . 10.1016/j.euroneuro.2015.12.027 . free . 45109526 . 11576/2631931 .
  7. Solinas M, Chauvet C, Lafay-Chebassier C, Jaafari N, Thiriet N . Environmental enrichment-inspired pharmacological tools for the treatment of addiction . Current Opinion in Pharmacology . 56 . 22–28 . February 2021 . 32966941 . 10.1016/j.coph.2020.09.001 . 221888359 . free .
  8. Chauvet C, Nicolas C, Thiriet N, Lardeux MV, Duranti A, Solinas M . Chronic stimulation of the tone of endogenous anandamide reduces cue- and stress-induced relapse in rats . The International Journal of Neuropsychopharmacology . 18 . 1 . pyu025 . December 2014 . 25522382 . 4368869 . 10.1093/ijnp/pyu025 .
  9. Web site: Kadmus Pharmaceuticals . https://web.archive.org/web/20051219040657/http://www.kadmuspharma.com/ . 19 December 2005 .

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