UR-12

UR-12
IUPAC ime
	7-metoksi-1-(2-morfolinoetil)-N-((1S,2S,4R)-1,3,3-trimetilbiciklo[2.2.1]heptan-2-il)-1H-indol-3-karboksamid
Pravni status
Pravni status	nije kontrolisan;
Identifikatori
CAS broj	. ; 501927-29-3 (2-metil derivat)
ATC kod	none
PubChem	CID 44307202
ChemSpider	26286811
Hemijski podaci
Formula	C26H37N3O3
Molarna masa	439,59 g/mol
	SMILES COC1=C(N(CCN2CCOCC2)C=C3C(N[C@H]4[C@@]5(C)CC[C@H](C5)C4(C)C)=O)C3=CC=C1; ;
	InChI InChI=1S/C26H37N3O3/c1-25(2)18-8-9-26(3,16-18)24(25)27-23(30)20-17-29(11-10-28-12-14-32-15-13-28)22-19(20)6-5-7-21(22)31-4/h5-7,17-18,24H,8-16H2,1-4H3,(H,27,30)/t18-,24-,26+/m1/s1 ; Key:VQGDMQICNRCQEH-UFKXBGGNSA-N ;

UR-12 (7-metoksi-1-(2-morfolinoetil)-N-((1S,2S,4R)-1,3,3-trimetilbiciklo[2.2.1]heptan-2-il)-1H-indol-3-karboksamid, ili N-(S)-Fenhil-1-(2-morfolinoetil)-7-metoksindol-3-karboksamid) je lek koji je razvila kompanija Bristol-Majers Skvib.^[1] On deluje kao relativno selektivni agonist perifernih kanabinoidnih receptora.^[2] UR-12 ima umeren afinitet za CB₂ receptore sa K_i vrednošću od 11 nM, i 22 puta niži afinitet za psihoaktivne CB₁ receptore, K_i od 245 nM. Indol 2-metilni derivat ima suprotni odnos afiniteta, K_i od 8 nM za CB₁ i 29 nM za CB₂,^[3]^[4] što je u kontrastu sa neobičnim trendom da 2-metil derivat ima povećanu selektivnost za CB₂ (cf. JWH-018 vs JWH-007, JWH-081 vs JWH-098).^[5]^[6]

On je hemijski blisko srodan sa jednim drugim indol-3-karboksamidnim sintetičkim kanabinoidom, Org 28611, koji ima različiti cikloalkilni supstituent na karboksamidu, i cikloheksilmetilnu grupu zamenjenu morfoliniletilom, kao i sa JWH-200 ili A-796,260. Otkriće ovih jedinjenja je dovelo do razvoja velikog broja srodnih indol-3-karboksamid kanabinoidnih liganda.^[7]^[8]^[9]^[10]

Reference

^ Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators in treating respiratory and non-respiratory diseases, WO 2001/58869
^ Rulin Zhao, Bei Wang, Hong Wu, John Hynes, Jr., Katerina Leftheris, Balu Balasubramanian, Joel C. Barrish and Bang-Chi Chen. Improved procedure for the preparation of 7-methoxy-2-methyl-1-(2-morpholinoethyl)-1H-indole-3-carboxylic acid, key intermediate in the synthesis of novel 3-amidoindole and indolopyridone cannabinoid ligands. ARKIVOC 2010 (vi):89-95.
^ Hynes, J.; Leftheris, K.; Wu, H.; Pandit, C.; Chen, P.; Norris, D. J.; Chen, B. C.; Zhao, R.; Kiener, P. A. (2002). „C-3 Amido-Indole cannabinoid receptor modulators”. Bioorganic & Medicinal Chemistry Letters. 12 (17): 2399—402. PMID 12161142. doi:10.1016/S0960-894X(02)00466-3.
^ Wrobleski, Stephen T.; Chen, Ping; Hynes, John; Lin, Shuqun; Norris, Derek J.; Pandit, Chennagiri R.; Spergel, Steven; Wu, Hong; Tokarski, John S. (2003). „Rational Design and Synthesis of an Orally Active Indolopyridone as a Novel Conformationally Constrained Cannabinoid Ligand Possessing Antiinflammatory Properties”. Journal of Medicinal Chemistry. 46 (11): 2110—6. PMID 12747783. doi:10.1021/jm020329q.
^ Huffman, J. W.; Padgett, L. W. (2005). „Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes”. Current Medicinal Chemistry. 12 (12): 1395—1411. PMID 15974991. doi:10.2174/0929867054020864.
^ Manera, C.; Tuccinardi, T.; Martinelli, A. (2008). „Indoles and Related Compounds as Cannabinoid Ligands”. Mini Reviews in Medicinal Chemistry. 8 (4): 370—387. PMID 18473928. doi:10.2174/138955708783955935.
^ Adam, J. M.; Cairns, J.; Caulfield, W.; Cowley, P.; Cumming, I.; Easson, M.; Edwards, D.; Ferguson, M.; Goodwin, R. (2010). „Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm. 1: 54. doi:10.1039/c0md00022a.
^ Kiyoi T, York M, Francis S, Edwards D, Walker G, Houghton AK, Cottney JE, Baker J, Adam JM (2010). „Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists”. Bioorganic & Medicinal Chemistry Letters. 20 (16): 4918—21. PMID 20634067. doi:10.1016/j.bmcl.2010.06.067.
^ Moir EM, Yoshiizumi K, Cairns J, Cowley P, Ferguson M, Jeremiah F, Kiyoi T, Morphy R, Tierney J, Wishart G, York M, Baker J, Cottney JE, Houghton AK, McPhail P, Osprey A, Walker G, Adam JM (2010). „Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists”. Bioorganic & Medicinal Chemistry Letters. 20 (24): 7327—30. PMID 21074434. doi:10.1016/j.bmcl.2010.10.061.
^ Blaazer, A. R.; Lange, J. H. M.; Van Der Neut, M. A. W.; Mulder, A.; Den Boon, F. S.; Werkman, T. R.; Kruse, C. G.; Wadman, W. J. (2011). „Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure–activity relationships, physicochemical properties and biological activity”. European Journal of Medicinal Chemistry. 46 (10): 5086—5098. PMID 21885167. doi:10.1016/j.ejmech.2011.08.021.

Literatura

John Hynes., Katerina Leftherisa, Hong Wua, Chennagiri Pandita, Ping Chena, Derek J. Norrisa, Bang-Chi Chenb, Rulin Zhaob, Peter A. Kienerc, Xiaorong Chenc, Lori A. Turkc, Vina Patil-Kootac, Kathleen M. Gilloolyc, David J. Shuterc and Kim W. Mclntyrec. C3 Amido-indole cannabinoid receptor modulators. Bioorganic and Medical Chemistry Letters. Volume 12 issue 17, 2 September 2002 pages 2399-2402
2. Frost, J. M.; Dart, M. J.; Tietje, K. R.; Garrison, T. R.; Grayson, G. K.; Daza, A. V.; El- Kouhen, O. F.; Yao, B. B. et al. (2010) . "Indol -3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity". Journal of Medicinal Chemistry 53 (1 ): 295. doi :10.1021/

jm901214q . PMID 19921781

3. Chin CL, Tovcimak AE, Hradil VP, Seifert TR, Hollingsworth PR, Chandran P, Zhu CZ, Gauvin D, Pai M, Wetter J, Hsieh GC, Honore P, Frost JM, Dart MJ, Meyer MD, Yao BB, Cox BF, Fox GB (January 2008). "Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI" . British

Journal of Pharmacology 153 (2) : 367–79. doi :10.1038/ sj.bjp .0707506 .PMC 2219521 . PMID 17965748

Vidi još

Spoljašnje veze

[1] Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators in treating respiratory and non-respiratory diseases, WO 2001/58869

[2] Rulin Zhao, Bei Wang, Hong Wu, John Hynes, Jr., Katerina Leftheris, Balu Balasubramanian, Joel C. Barrish and Bang-Chi Chen. Improved procedure for the preparation of 7-methoxy-2-methyl-1-(2-morpholinoethyl)-1H-indole-3-carboxylic acid, key intermediate in the synthesis of novel 3-amidoindole and indolopyridone cannabinoid ligands. ARKIVOC 2010 (vi):89-95.

[3] Hynes, J.; Leftheris, K.; Wu, H.; Pandit, C.; Chen, P.; Norris, D. J.; Chen, B. C.; Zhao, R.; Kiener, P. A. (2002). „C-3 Amido-Indole cannabinoid receptor modulators”. Bioorganic & Medicinal Chemistry Letters. 12 (17): 2399—402. PMID 12161142. doi:10.1016/S0960-894X(02)00466-3.

[4] Wrobleski, Stephen T.; Chen, Ping; Hynes, John; Lin, Shuqun; Norris, Derek J.; Pandit, Chennagiri R.; Spergel, Steven; Wu, Hong; Tokarski, John S. (2003). „Rational Design and Synthesis of an Orally Active Indolopyridone as a Novel Conformationally Constrained Cannabinoid Ligand Possessing Antiinflammatory Properties”. Journal of Medicinal Chemistry. 46 (11): 2110—6. PMID 12747783. doi:10.1021/jm020329q.

[5] Huffman, J. W.; Padgett, L. W. (2005). „Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes”. Current Medicinal Chemistry. 12 (12): 1395—1411. PMID 15974991. doi:10.2174/0929867054020864.

[6] Manera, C.; Tuccinardi, T.; Martinelli, A. (2008). „Indoles and Related Compounds as Cannabinoid Ligands”. Mini Reviews in Medicinal Chemistry. 8 (4): 370—387. PMID 18473928. doi:10.2174/138955708783955935.

[7] Adam, J. M.; Cairns, J.; Caulfield, W.; Cowley, P.; Cumming, I.; Easson, M.; Edwards, D.; Ferguson, M.; Goodwin, R. (2010). „Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm. 1: 54. doi:10.1039/c0md00022a.

[pmid20634067-8] Kiyoi T, York M, Francis S, Edwards D, Walker G, Houghton AK, Cottney JE, Baker J, Adam JM (2010). „Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists”. Bioorganic & Medicinal Chemistry Letters. 20 (16): 4918—21. PMID 20634067. doi:10.1016/j.bmcl.2010.06.067.

[pmid21074434-9] Moir EM, Yoshiizumi K, Cairns J, Cowley P, Ferguson M, Jeremiah F, Kiyoi T, Morphy R, Tierney J, Wishart G, York M, Baker J, Cottney JE, Houghton AK, McPhail P, Osprey A, Walker G, Adam JM (2010). „Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists”. Bioorganic & Medicinal Chemistry Letters. 20 (24): 7327—30. PMID 21074434. doi:10.1016/j.bmcl.2010.10.061.

[10] Blaazer, A. R.; Lange, J. H. M.; Van Der Neut, M. A. W.; Mulder, A.; Den Boon, F. S.; Werkman, T. R.; Kruse, C. G.; Wadman, W. J. (2011). „Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure–activity relationships, physicochemical properties and biological activity”. European Journal of Medicinal Chemistry. 46 (10): 5086—5098. PMID 21885167. doi:10.1016/j.ejmech.2011.08.021.

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