Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 8, 2008, Pages 2562-2566

  Fish, Paul V ^a   Deur, Christopher ^b   Gan, Xinmin ^b   Greene, Keri ^b   Hoople, David ^a   Mackenny, Malcolm ^a   Para, Kimberly S ^b   Reeves, Keith ^a   Ryckmans, Thomas ^a   Stiff, Cory ^b   Stobie, Alan ^a   Wakenhut, Florian ^a   Whitlock, Gavin A ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

^b PFIZER INC   (United States)

Author keywords

Enzyme catalysed resolution; Morpholine; Serotonin and noradrenaline reuptake inhibitor; SNRI

Indexed keywords

CARBOXYLIC ACID DERIVATIVE; CYTOCHROME P450 1A2; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; DULOXETINE; FUNCTIONAL GROUP; MONOAMINE; MORPHOLINE DERIVATIVE; NORADRENALIN; PF 734629; REBOXETINE; SEROTONIN; SEROTONIN NORADRENALIN REUPTAKE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BIOLOGICAL ACTIVITY; CENTRAL NERVOUS SYSTEM; CONTROLLED STUDY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOMER; ENZYME MECHANISM; HUMAN; HUMAN CELL; INTERSTITIAL FLUID; LIPOPHILICITY; MEMBRANE PERMEABILITY; NONHUMAN; PHYSICAL CHEMISTRY; PREFRONTAL CORTEX; RACEMIC MIXTURE; RAT; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

CELLS, CULTURED; DRUG DESIGN; HUMANS; LIVER; MOLECULAR STRUCTURE; MORPHOLINES; NOREPINEPHRINE; SEROTONIN; SEROTONIN UPTAKE INHIBITORS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 41849121199     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.03.050     Document Type: Article

References (34)

1. Montgomery S. Int. J. Psych. Clin. Pract. 10 (2006) 5
2. Baldwin D.S. Int. J. Psych. Clin. Pract. 10 (2006) 12
3. Wernicke J.F., Iyengar S., and Ferrer-Garcia M.D. Curr. Drug Therapy 2 (2007) 161
4. Jackson S. Curr. Med. Res. Opin. 21 (2005) 1669
5. For recent reviews of new chemical entities, see:. Walter M.W. Drug Dev. Res. 65 (2005) 97
6. Huang Y., and Williams W.A. Expert Opin. Ther. Patents 17 (2007) 889
7. Thor K.B., Kirby M., and Viktrup L. Int. J. Clin. Pract. 61 (2007) 1349
8. Steers W.D., Herschorn S., Kreder K.J., Moore K., Strohbehn K., Yalcin I., and Bump R.C. BJU Int. 100 (2007) 337
9. Fray M.J., Bish G., Brown A.D., Fish P.V., Stobie A., Wakenhut F., and Whitlock G.A. Bioorg. Med. Chem. Lett. 16 (2006) 4345
10. Fray M.J., Bish G., Fish P.V., Stobie A., Wakenhut F., and Whitlock G.A. Bioorg. Med. Chem. Lett. 16 (2006) 4349
11. Fish P.V., Fray M.J., Stobie A., Wakenhut F., and Whitlock G.A. Bioorg. Med. Chem. Lett. 17 (2007) 2022
12. Whitlock G.A., Blagg J., and Fish P.V. Bioorg. Med. Chem. Lett. 18 (2008) 596
13. Hajos M., Fleishaker J.C., Filipiak-Reisner J.K., Brown M.T., and Wong E.H.F. CNS Drug Rev. 10 (2004) 23
14. Fish, P. V.; Mackenny, M. C.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. WO Patent 105100, 2005.
15. Mahar Doan K.M., Humphreys J.E., Webster L.O., Wring S.A., Shampine L.J., Serabjit-Singh C.J., Adkison K.K., and Polli J.W. J. Pharm. Exp. Ther. 303 (2002) 1029
16. a: measured ionisation constant; HBD: H-bond donor count (NH+OH); HBA: H-bond acceptor count (N+O); PSA: polar surface area.
17. Boot J., Cases M., Clark B.P., Findlay J., Gallagher L.H., Man T., Montalbetti C., Rathmell R.E., Rudyk H., Walter M.W., Whatton M., and Wood V. Bioorg. Med. Chem. Lett. 15 (2005) 699
18. For racemic syntheses, see:. Melloni P., Carniel G., Della Torre A., Bonsignori A., Buonamici M., Pozzi O., Ricciardi S., and Rossi A.C. Eur. J. Med. Chem. 19 (1984) 235
19. reference 12.
20. Henegar K.E., Ball C.T., Horvath C.M., Maisto K.D., and Mancini S.E. Org. Proc. Res. Dev. 11 (2007) 346
21. For an asymmetric synthesis of (+)-(S,S)-reboxetine, see:. Brenner E., Baldwin R.M., and Tamagnan G. Org. Lett. 7 (2005) 937
22. King F.D., Hadley M.S., Joiner K.T., Martin R.T., Sanger G.J., Smith D.M., Smith G.E., Smith P., Turner D.H., and Watts E.A. J. Med. Chem. 36 (1993) 683
23. Lipase Candida rugosa is commercially available from Sigma (catalogue number: L-1754; 1140 U/mg).
24. Enantioselectivities were determined by chiral HPLC (Chiralcel OJ-H, 250 × 4.6 mm; hexane/0.1% TFA in EtOH, 80:20 isocratic, 1 mL/min).
25. 3H salt (mp 182 °C). Crystallographic data (excluding structure factors) for the structures in this letter have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC680331. Copies of the data can be obtained free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK.
26. Walsh G.M. Exp. Opin. Drug Safety 1 (2002) 225
27. For an analysis of the influence of drug lipophilicity on off-target pharmacology and in vivo toxicological outcomes, see:. Leeson P.D., and Springthorpe B. Nature Rev. Drug Dis. 6 (2007) 881
28. Hughes, J. D.; Blagg, J.; Bailey, S.; De Crescenzo, G. A.; Dalvie, D.; Devraj, R. V.; Doubovetzky, M.; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Grant, D.; Greene, N.; Huang, E.; Kreiger-Burke, T.; Lee, L.; Loesel, J.; Nahas, K.; Price, D. A.; Wager, T.; Whiteley, L.; Zhang, Y. Correlations between compound physicochemical properties and in vivo toxicological outcomes: Comprehensive analysis of a 245 compound data set. Nat. Biotech., 2008, in press.
29. 2+) was performed by CEREP, France.
30. Deecher D.C., Beyer C.E., Johnston G., Bray J., Shah S., Abou-Gharbia M., and Andree T.H. J. Pharm. Exp. Ther. 318 (2006) 657
31. i = 6 nM (n = 2).
32. +); 100% e.e. by chiral HPLC.
33. For an accompanying paper, see: Xu, W.; Gray, D. L.; Glase, S. A.; Barta, N. S. Bioorg. Med. Chem. Lett. 2008, submitted for publication.
34. Target compounds were tested for their ability to inhibit specific binding of selective radioligands at the human 5-HT, NA and DA transporters utilising scintillation proximity assay (SPA) technology and cellular membrane preparations generated from recombinant HEK293 cells expressing a single monoamine transporter. For experimental details of the assay conditions, see: Andrews, M. D.; Brown, A. D.; Fish, P. V.; Fray, M. J.; Lansdell, M. I.; Ryckmans, T.; Stobie, A.; Wakenhut, F.; Gray, D. L. F. WO Patent 064351, 2006, p 56-59.