Tetrahydronaphthalene-derived amino alcohols and amino ketones as potent and selective inhibitors of the delayed rectifier potassium current I Ks

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 1, 2004, Pages 99-102

  Ahmad, Saleem ^a   Doweyko, Lidia ^a   Ashfaq, Aaila ^a   Ferrara, Francis N ^a   Bisaha, Sharon N ^a   Schmidt, Joan B ^a   DiMarco, John ^a   Conder, Mary Lee ^a   Jenkins West, Tonya ^a   Normandin, Diane E ^a   Russell, Anita D ^a   Smith, Mark A ^a   Levesque, Paul C ^a   Lodge, Nicholas J ^a   Lloyd, John ^a   Stein, Philip D ^a   Atwal, Karnail S ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOALCOHOL; AMINOKETONE; TETRALIN DERIVATIVE;

ARTICLE; CONCENTRATION RESPONSE; DRUG ACTIVITY; DRUG POTENCY; DRUG STRUCTURE; IN VITRO STUDY; POTASSIUM CURRENT; STRUCTURE ACTIVITY RELATION;

EID: 0347517815     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2003.10.003     Document Type: Article

References (21)

1. Colatsky T.J., Follmer C.H., Starmer C.F. Circulation. 82:1990;2235.
2. Sanguinetti M.C., Jurkiewicz N.K. J. Gen. Physiol. 96:1990;195.
3. Sanguinetti M.C., Jiang C., Curran M.E., Keating M.T. Cell. 81:1995;299.
4. (a) Barhanin J., Lesage F., Guillemare E., Fink M., Lazdunski M., Romey G. Nature. 384:1996;78.
5. (b) Sanguinetti M.C., Curran M.E., Zou A., Shen J., Spector P.S., Atkinson D.L., Keating M.T. Nature. 384:1996;80.
6. Curran M.E., Splawski I., Timothy K.W., Vincent G.M., Green E.D., Keating M.E. Cell. 80:1995;795.
7. Jurkiewicz N.K., Sanguinetti M.C. Circ. Res. 72:1993;75.
8. (a) Lynch J.J., Houle M.S., Stump G.L., Wallace A.A., Gilberto D.B., Jahansouz H., Smith G.R., Tebben A.J., Liverton N.J., Selnick H.G., Claremon D.A., Billman G.E. Circulation. 100:1999;1917.
9. (b) Stump G.L., Smith G.R., Tebben A.J., Jahansouz H., Salata J.J., Selnick H.G., Claremon D.A., Lynch J.J. J. Cardio. Pharmac. 42:2003;105.
10. (a) Butcher J.W., Liverton N.J., Claremon D.A., Freidinger R.M., Jurkiewicz N.K., Lynch J.J., Salata J.J., Wang J., Dieckhaus C.M., Slaughter D.E., Vyas K. Bioorg. Med. Chem. Lett. 13:2003;1165.
11. (b) Selnick H.G., Liverton N.J., Baldwin J.J., Butcher J.W., Claremon D.A., Elliot J.M., Freidinger R.M., King S.A., Libby B.E., McIntyre C.J., Pribush D.A., Remy D.C., Smith G.R., Tebben A.J., Jurkiewicz N.K., Lynch J.J., Salata J.J., Sanguinetti M.A., Siegl P.K.S., Slaughter D.E., Vyas K. J. Med. Chem. 40:1997;3865.
12. (c) Gerlach U., Brendel J., Lang H.-J., Paulus E.F., Weidmann K., Brueggemann A., Busch A.E., Suessbrich H., Bleich M., Greger R. J. Med. Chem. 44:2001;3831.
13. (d) Gerlach U. Drugs of the Future. 26:2001;473.
14. Lloyd J., Schmidt J.B., Rovnyak G., Ahmad S., Atwal K.S., Bisaha S.N., Doweyko L.M., Stein P.D., Traeger S.C., Mathur A., Conder M.L., DiMarco J., Harper T.W., Jenkins-West T., Levesque P.C., Normandin D.E., Russell A.D., Serafino R.P., Smith M.A., Lodge N.J. J. Med. Chem. 44:2001;3764.
15. Screening of the internal compound database was carried out in guinea pig ventricular myocytes using voltage clamp techniques: Lodge N.J., Smith M.A. Naunyn-Schmiedeberg's Arch. Pharmaco. 354:1996;444.
16. Ahmad, S., Stein, P. D., Ferrara, F. N., Atwal, K. S. WO 9836749.
17. Durden J.A. Jr. J. Agr. Food Chem. 19:1971;432.
18. Dess D.B., Martin J.C. J. Am. Chem. Soc. 113:1991;7277.
19. Workup under strongly acidic conditions affords an olefinic product derived from dehydration of 11. Typically, the reaction is quenched by adding 0.1 N HCl, extracted with ethyl acetate and concentrated in vacuo at rt to afford a diglyme solution of 11 which is used as such in subsequent steps.
20. Lodge N.J., Normandin D.E. J. Mol. Cell. Cardiol. 29:1997;3211.
21. Compounds 7b, 8a, 8b and 10d were obtained in enantiomerically pure form by subjecting the corresponding racemic mixtures to chromatography on a CHIRALCEL® OD column (hexane-isopropanol-triethylamine 90:10:0.2-80:20:0.2). The more potent enantiomers for compounds 7b and 8b, and the less potent enantiomers for 8a and 10d, are eluted first. The absolute stereochemistry of the more potent enantiomer for 7b was determined to be R,R (see Scheme 1) by X-ray crystallography of 1:1 salt with R-mandelic acid. Compound 14a was resolved by CHIRALPAK® AD column (hexane-isopropanol-triethylamine 80:20:0.2, the faster moving enantiomer is more active).