Benzimidazole- and indole-substituted 1,3′-bipyrrolidine benzamides as histamine H3 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 3, 2010, Pages 1237-1240

  Cole, Derek C ^a   Gross, Jonathan L ^b   Comery, Thomas A ^b   Aschmies, Suzan ^b   Hirst, Warren D ^b   Kelley, Cody ^b   Kim, Ji In ^b   Kubek, Katie ^b   Ning, Xiaoping ^b   Platt, Brian J ^b   Robichaud, Albert J ^b   Solvibile, William R ^b   Stock, Joseph R ^a   Tawa, Gregory ^b   Williams, Marla J ^b   Ellingboe, John W ^a  

^a WYETH RESEARCH   (United States)

^b PFIZER INC   (United States)

Author keywords

Histamine H3 receptor antagonist; Histamine H3 receptor inverse agonist

Indexed keywords

5 (4 CYANOPHENYL) 2 [2 (2 METHYL 1 IMIDAZOLIDINYL)ETHYL]BENZOFURAN; 6 (3 CYCLOBUTYL 2,3,4,5 TETRAHYDRO 1H 3 BENZAZEPIN 7 YLOXY) N METHYLNICOTINAMIDE; CIPROXIFAN; FUB 181; HISTAMINE H3 RECEPTOR ANTAGONIST; JNJ 5207852; UNCLASSIFIED DRUG; BENZAMIDE DERIVATIVE; BENZIMIDAZOLE; BENZIMIDAZOLE DERIVATIVE; HISTAMINE H3 RECEPTOR; INDOLE DERIVATIVE; PROTEIN BINDING; PYRROLIDINE DERIVATIVE;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; BRAIN; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG POTENCY; DRUG SCREENING; EMBRYO; FLUID INTAKE; HUMAN; HUMAN CELL; NONHUMAN; PLASMA; RAT; RECOGNITION; STRUCTURE ACTIVITY RELATION; ANIMAL; BLOOD; CACO 2 CELL LINE; CELL LINE; CHEMISTRY; COMPARATIVE STUDY; METABOLISM;

ANIMALS; BENZAMIDES; BENZIMIDAZOLES; CACO-2 CELLS; CELL LINE; HISTAMINE H3 ANTAGONISTS; HUMANS; INDOLES; PROTEIN BINDING; PYRROLIDINES; RATS; RECEPTORS, HISTAMINE H3;

EID: 74049129463     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.11.122     Document Type: Article

References (31)

1. Arrang J.M., Garbarg M., and Schwartz J.C. Nature 302 (1983) 832
2. Lovenberg T.W., Roland B.L., Wilson S.J., Jiang X., Pyati J., Huvar A., Jackson M.R., and Erlander M.G. Mol. Pharmacol. 55 (1999) 1101
3. Hough L.B. Mol. Pharmacol. 59 (2001) 415
4. Hill S.J., Ganellin C.R., Timmerman H., Schwartz J.C., Shankley N.P., Young J.M., Schunack W., Levi R., and Haas H.L. Pharmacol. Rev. 49 (1997) 253
5. Hofstra C.L., Desai P.J., Thurmond R.L., and Fung-Leung W.P. J. Pharmacol. Exp. Ther. 305 (2003) 1212
6. Panula P., Rinne J., Kuokkanen K., Eriksson K.S., Sallmen T., Kalimo H., and Relja M. Neuroscience 82 (1998) 993
7. Blandina P., Giorgetti M., Bartolini L., Cecchi M., Timmerman H., Leurs R., Pepeu G., and Giovannini M.G. Br. J. Pharmacol. 119 (1996) 1656
8. Prast H., Argyriou A., and Philippu A. Brain Res. 734 (1996) 316
9. Miyazaki S., Onodera K., Imaizumi M., and Timmerman H. Life Sci. 61 (1997) 355
10. Meguro K., Yanai K., Sakai N., Sakurai E., Maeyama K., Sasaki H., and Watanabe T. Pharmacol. Biochem. Behav. 50 (1995) 321
11. Fox G.B., Pan J.B., Esbenshade T.A., Bennani Y.L., Black L.A., Faghih R., Hancock A.A., and Decker M.W. Behav. Brain Res. 131 (2002) 151
12. Komater V.A., Browman K.E., Curzon P., Hancock A.A., Decker M.W., and Fox G.B. Psychopharmacology (Berl.) 167 (2003) 363
13. Komater V.A., Buckley M.J., Browman K.E., Pan J.B., Hancock A.A., Decker M.W., and Fox G.B. Behav. Brain Res. 159 (2005) 295
14. Celanire S., Wijtmans M., Talaga P., Leurs R., and de Esch I.J. Drug Discovery Today 10 (2005) 1613
15. Esbenshade T.A., Krueger K.M., Miller T.R., Kang C.H., Denny L.I., Witte D.G., Yao B.B., Fox G.B., Faghih R., Bennani Y.L., Williams M., and Hancock A.A. J. Pharmacol. Exp. Ther. 305 (2003) 887
16. Stark H., Huls A., Ligneau X., Purand K., Pertz H., Arrang J.M., Schwartz J.C., and Schunack W. Arch. Pharm. (Weinheim) 331 (1998) 211
17. Yang R., Hey J.A., Aslanian R., and Rizzo C.A. Pharmacology 66 (2002) 128
18. Apodaca R., Dvorak C.A., Xiao W., Barbier A.J., Boggs J.D., Wilson S.J., Lovenberg T.W., and Carruthers N.I. J. Med. Chem. 46 (2003) 3938
19. Cowart M., Pratt J.K., Stewart A.O., Bennani Y.L., Esbenshade T.A., and Hancock A.A. Bioorg. Med. Chem. Lett. 14 (2004) 689
20. Heightman, T. D. WO2004035544, 2004.
21. HEK293T cells expressing the human cloned histamine H3 receptor were harvested in phosphate-buffered saline (PBS) and pelleted by centrifugation at 1000g for 5 min at 4 °C and membranes were prepared by homogenizing the cell pellets in ice-cold 50 mM Tris-HCl buffer, pH 7.4 and 0.5 mM EDTA for approximately 30 s using a Polytron homogenizer. The homogenates were centrifuged at 40,000g for 30 min at 4 °C, and the resulting pellet was re-homogenized and centrifuged as described above. The membranes were finally resuspended in 50 mM Tris-HCl buffer, pH 7.4 at a concentration of approximately 1 mg protein/mL, and were stored at -70 °C until use. Receptor binding studies were carried out on these membranes in 50 mM Tris-HCl buffer, pH 7.4, at room temperature. Assays consisted of 100 μL of displacing compound (final concentration of 0.05 nM-500 nM) or buffer, 20 μL of [3H]R-α-methylhistamine at a final concentration of 5 nM and the reaction was initiated by the addition of 100 mL of human H3 receptor membranes (30 μg of protein/well). Nonspecific binding was determined in the presence of 10 mM clobenpropit. The experiments were terminated by rapid filtration through a GF/B filter plate (presoaked in 0.1% (v/v) polyethyleneimine), and then the filters were washed with ice-cold buffer (50 mM Tris-HCl). Filters were dried and then 25 μL of Microscint 20 was added to each well. Radioactivity was determined by liquid scintillation spectrometry using a Packard TopCount.
22. 2+-free) containing 500 μM IBMX. Cells were detached, by gentle tapping, and resuspended in the same buffer. 2000 cells/well were incubated with 1 μM histamine, 10 μM forskolin and test compounds (0.03 nM-10 μM) in a total volume of 30 μL in 96-well plates for 30 min at 30 °C. Cyclic AMP levels were then measured using the HitHunter cAMP kit (DiscoveRx, Fremont, CA) according to the manufacturer's instructions. Chemiluminescent signals were detected using a Packard TopCount. Data were analyzed using Prizm.
23. Kerns E.H., and Di L. Drug Discovery Today 8 (2003) 316
24. Di L., Kerns E.H., Fan K., McConnell O.J., and Carter G.T. Eur. J. Med. Chem. 38 (2003) 223
25. Keseru G.M., and Makara G.M. Nat. Rev. Drug Disc. 8 (2009) 203
26. Clark D.E. Drug Discovery Today (2003) 927
27. Lobell M., Molnar L., and Keseru G.M. J. Pharm. Sci. 92 (2003) 360
28. Clapham J., and Kilpatrick G.J. Eur. J. Pharmacol. 232 (1993) 99
29. Kraly F.S., Tribuzio R.A., Kim Y.M., Keefe M.E., and Finkell J. Physiol. Behav. 58 (1995) 1091
30. Blandina P., Giorgetti M., Cecchi M., Leurs R., Timmerman H., and Giovannini M.G. Inflamm. Res. 45 (1996) S54
31. Pascoli V., Boer-Saccomani C., and Hermant J.F. Psychopharmacology (Berl) 202 (2009) 141