Structure-activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 12, 2007, Pages 3367-3372

  Xie, Yun Feng ^a   Lake, Kirk ^a   Ligsay, Kathleen ^a   Komandla, Mallareddy ^a   Sircar, Ila ^a   Nagarajan, Gobi ^a   Li, Jian ^a   Xu, Kui ^a   Parise, Jason ^a   Schneider, Lisa ^a   Huang, Ding ^a   Liu, Juping ^a   Dines, Kevin ^a   Sakurai, Naoki ^a   Barbosa, Miguel ^a   Jack, Rick ^a  

^a Tanabe Research Laboratories   (United States)

Author keywords

CCR1 antagonist; Chemokine receptor 1; Diaminocyclobutenedione

Indexed keywords

1 [5 CHLORO 2 [2 [4 (4 FLUOROBENZYL) 2 METHYL 1 PIPERAZINYL] 2 OXOETHOXY]PHENYL]UREA; 3 AMINO 4 [2 [2 (4 BENZYLPIPERAZIN 1 YL) 2 OXOETHOXY]PHENYLAMINO]CYCLOBUTENEDIONE DERIVATIVE; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR1; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTHRITIS; ARTICLE; CROSS REACTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; MALE; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ARTHRITIS, EXPERIMENTAL; BENZYL COMPOUNDS; BINDING SITES; COLLAGEN; CYCLOBUTANES; DISEASE MODELS, ANIMAL; DRUG DESIGN; MALE; MICE; MICE, INBRED BALB C; RECEPTORS, CHEMOKINE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 34249275319     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.03.104     Document Type: Article

References (18)

1. Charo I.F., and Ransohoff R.M. N. Eng. J. Med. 354 (2006) 610
2. Tarrant T.K., and Patel D.D. Pathophysiology 13 (2006) 1
3. Saeki T., and Naya A. Curr. Pharm. Des. 9 (2003) 1201
4. Katschke K.J., Rottman J.B., et al. Arthritis Rheum. 44 (2001) 1022
5. Chintalacharuvu S.R., Wang J.X., Giaconia J.M., and Venkataraman C. Immunol. Lett. 100 (2005) 202
6. Rottman J.B., Slavin A.J., Silva R., Weiner H.L., Gerard C.G., and Hancock W.W. Eur. J. Immunol. 30 (2000) 2372
7. Gao W., Topham P.S., King J.A., Smiley S.T., Csizmadia V., Lu B., Gerard C.J., and Hancock W.W. J. Clin. Invest. 105 (2000) 35
8. Shahrara S., Proudfoot A.E., Woods J.M., Ruth J.H., Amin M.A., Park C.C., Haas C.S., Pope R.M., Haines G.K., Zha Y.Y., et al. Arthritis Rheum. 52 (2005) 1907
9. Plater-Zyberk C., Hoogewerf A.J., Proudfoot A.E., Power C.A., and Wells T.N. Immunol. Lett. 57 (1997) 117
10. Haringman J.J., Kraan M.C., Smeets T.J.M., Zwinderman K.H., and Tak P.P. Ann. Rheum. Dis. 62 (2003) 715
11. Lians M., Mallari C., Rosser M., Ng H.P., May K., Monahan S., et al. J. Biol. Chem. 175 (2000) 19000
12. Revesz L., Bollbuck B., Buhl T., Eder J., Esser R., Feifel R., Heng R., and Hiestand P. Bioorg. Med. Chem. Lett. 15 (2005) 5160
13. Revesz L., Bollbuck B., Buhl T., Dawson J., Feifel R., Heng R., Hiestand P., Schlapbach A., Waelchli R., and Loetscher P. Lett. Drug Des. Discov. 3 (2006) 689
14. Naya A., Sagara Y., Ohwaki K., Saeki T., Ichikawa D., Iwasawa Y., Noguchi K., and Ohtake N. J. Med. Chem. 44 (2001) 1429
15. Kath J., Brissette W., Brown M., Conklyn M., DiRico A., Dorff P., Gladue R., Lillie B., Lira P., et al. Bioorg. Med. Chem. Lett. 14 (2004) 2169
16. Schwender, C. F.; Mackay, C. R.; Pinto, J. C.; Newman, W. WO9802151.
17. 2, and 0.5% BSA (Hepes-BSA). The mixture was incubated at room temperature for 90 min and transferred to 96-well glass fiber filter plate pre-coated with 0.5% polyethyleneimine (PEI). Cells were separated by vacuum aspiration and washed twice with Hepes-BSA + 0.5 M NaCl. Radioactivity was measured on TopCount plate reader with 40 μl Microscint 40 scintillation fluid. Non-specific binding was determined in the presence of 150 nM unlabeled human MIP-1α.
18. 6/ml. The calcein-labeled cells were then mixed with compound or DMSO control for 30 min at 37 °C. and loaded in the wells on the top of a 5-μm polycarbonate filter in a 96-well Boyden chamber (NeuroProbe), in which 0.5 nM human MIP-1α with or without compounds had been added to the corresponding wells beneath the filter. The sealed chamber was incubated for 2 h at 37 °C. Non-migrated cells on top of the filter were removed by wiping. The filter was reversed and read at 485/530 nm emission/excitation wavelengths with FlexStation II (Molecular Devices).