Synthesis and biological activity of piperazine-Based dual MMP-13 and TNF-α converting enzyme inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 19, 2003, Pages 3243-3246

  Letavic, Michael A ^a   Barberia, John T ^a   Carty, Thomas J ^a   Hardink, Joel R ^a   Liras, Jennifer ^a   Lopresti Morrow, Lori L ^a   Mitchell, Peter G ^a   Noe, Mark C ^a   Reeves, Lisa M ^a   Snow, Sheri L ^a   Stam, Ethan J ^a   Sweeney, Francis J ^a   Vaughn, Marcie L ^a   Yu, Chul H ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZYL DERIVATIVE; ENZYME INHIBITOR; HYDROXAMIC ACID DERIVATIVE; INFLIXIMAB; MATRIX METALLOPROTEINASE 1 INHIBITOR; MATRIX METALLOPROTEINASE 13 INHIBITOR; NITROGEN; PIPERAZINE; PIPERAZINE 2 HYDROXAMIC ACID; TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; DRUG ACTIVITY; IN VIVO STUDY; NONHUMAN; OBSERVATION; RAT;

EID: 10744225421     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00666-8     Document Type: Article

References (18)

1. Beutler B.A. J. Rheumatol., Supp. 26:1999;16.
2. Feldmann M., Ravinder N.M. Annu. Rev. Immunol. 19:2001;163.
3. Black R.A., Rauch C.T., Kozlosky C.J., Peschon J.J., Slack J.L., Wolfson M.F., Castner B.J., Stocking K.L., Reddy P., Srinivasan S., Nelson N., Boiani N., Schooley K.A., Gerhart M., Davis R., Fitzner J.N., Johnson R.S., Paxton R.J., March C.J., Cerretti D.P. Nature. 385:1997;729.
4. Moss M.L., Jin S.-L. C., Milla M.E., Burkhart W., Carter H.L., Chen W.-J., Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R., Kost T.A., Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G., Mitchell J., Moyer M., Pahel G., Rocque W., Overton L.K., Schoenen F., Seaton T., Su J.-L., Warner J., Willard D., Becherer J.D. Nature. 385:1997;733.
5. Subsequent to the completion of the research described in this manuscript using recombinant-TACE (r-TACE) a patent was issued to the Immunex Corporation covering the preparation of the TACE construct. US Patent Number 5,830,742.
6. Letavic M.A., Axt M.Z., Barberia J.T., Carty T.J., Danley D.E., Geoghegan K.F., Halim N.S., Hoth L.R., Kamath A.V., Laird E.R., Lopresti-Morrow L.L., McClure K.F., Mitchell P.G., Natarajan N., Noe M.C., Pandit J., Reeves L., Schulte G.K., Snow S.L., Sweeney F.J., Tan D.H., Yu C.H. Bioorg. Med. Chem. Lett. 12:2002;1387.
7. Chen J.M., Jin G., Sung A., Levin J.I. Bioorg. Med. Chem. Lett. 12:2002;1195.
8. Levin J.I., Chen J.M., Du M.T., Nelson F.C., Killar L.M., Skala S., Sung A., Jin G., Cowling R., Barone D., March C.J., Mohler K.M., Black R.A., Skotnicki J.S. Bioorg. Med. Chem. Lett. 12:2002;1199.
9. Conway J.G., Andrews R.C., Beaudet B., Bickett D.M., Boncek V., Brodie T.A., Clark R.L., Crumrine R.C., Leenitzer M.A., Mcdougald D.L., Han B., Hedeen K., Lin P., Milla M., Moss M., Pink H., Rabinowitz M.H., Tippin T., Scates P.W., Selph J., Stimpson S.A., Warner J., Becherer J.D. J. Pharm. Exp. Ther. 298:2001;900.
10. Robinson R.P., Laird E.R., Blake J.F., Bordner J., Donahue K.M., Lopresti-Morrow L.L., Mitchell P.G., Reese M.R., Reeves L.M., Stam E.J., Yocum S.A. J. Med. Chem. 43:2000;2293.
11. Mitchell P.G., Magna H.A., Reeves L.M., Lopresti-Morrow L.L., Yocum S.A., Rosner P.J., Geoghegan K.F., Hambor J.E. J. Clin. Invest. 97:1996;761.
12. Nelson F.C., Santos E.D., Levin J.I., Chen J.M., Skotnicki J.S., DiJoseph J.F., Sharr M.A., Sung A., Killar L.M., Cowling R., Jin G., Roth C., Albright J.D. Bioorg. Med. Chem. Lett. 12:2002;2867.
13. Cheng M., De B., Pikul S., Almstead N.G., Natchus M.G., Anastasio M.V., McPhail S.J., Snider C.E., Taiwo Y.O., Chen L., Dunaway M., Gu F., Dowty M.E., Mieling G.E., Janusz M.J., Wang-Weigand S. J. Med. Chem. 43:2000;369.
14. Han H., Yoon J., Janda K.D. J. Org. Chem. 63:1998;2045.
15. The TACE, human whole blood and MMP-1 assays described in this work were performed as detailed in ref 6.
16. Compounds were assayed versus MMP-13 using a quenched fluorescent peptide substrate assay as described in Bickett D.M., Green M.D., Berman J., Dezube M., Howe A.S., Brown P.J., Roth J.T., McGeehan G.M. Anal. Biochem. 212:1993;58.
17. In this model, the compounds are administered orally as a suspension of 0.5% methylcellulose. LPS injection leads to a systemic response, accompanied by release of TNF-α into the plasma. At 150 min post dose, plasma samples are acquired and cytokine levels are determined by ELISA.
18. The compound is administered iv; at a dose of 5 mg/kg as a solution in glycerol-formal.