The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 5, 2011, Pages 1376-1381

  De Savi, Chris ^a   Pape, Andrew ^a   Cumming, John G ^a   Ting, Attilla ^a   Smith, Peter D ^a   Burrows, Jeremy N ^a   Mills, Mark ^a   Davies, Chris ^a   Lamont, Scott ^a   Milne, David ^a   Cook, Calum ^a   Moore, Peter ^a   Sawyer, Yvonne ^a   Gerhardt, Stefan ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

ADAM TS4; Aggrecanases; Cyp inhibition; MMP 13; Osteoarthritis; Reverse hydroxamates

Indexed keywords

2 BROMO 4 FLUORO PHENYL; 2 CHLORO 4 (TRIFLUOROMETHYL)PHENYL; 2 CHLORO 4 METHYLSULFONYL PHENYL; 2 CHLORO 5 FLUOROPHENYL; 2,5 DIMETHYL 3 PYRIDYL; 2,5 DIMETHYL 4 PYRIDYL; 2,5 DIMETHYLPHENYL; 2,5 DIMETHYLPYRAZOL 3 YL; 3 CHLORO 5 (TRIFLUOROMETHYL) 2 PYRIDYL; 3 METHYL 5 (TRIFLUOROMETHYL) 2 PYRIDYL; 3,5 DIMETHYLISOTHIAZOL 4 YL; 3,5 DIMETHYLISOXAZOL 4 YL; 4 CHLORO 2 METHYL PHENYL; 4 FLUORO 2 (TRIFLUOROMETHYL)PHENYL; 4 FLUORO 2 METHYL PHENYL; 4,6 DIMETHYL 3 PYRIDYL; AGGRECANASE 1; AGGRECANASE 2; COLLAGENASE 3; CYTOCHROME P450; METALLOPROTEINASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; DRUG BINDING; DRUG CLEARANCE; DRUG DESIGN; DRUG METABOLISM; DRUG SELECTIVITY; DRUG SYNTHESIS; IC 50; OSTEOARTHRITIS; STRUCTURE ACTIVITY RELATION;

ADAM PROTEINS; ANTI-INFLAMMATORY AGENTS; DRUG DESIGN; ENZYME ACTIVATION; FORMAMIDES; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; OSTEOARTHRITIS; PROCOLLAGEN N-ENDOPEPTIDASE; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79951692827     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.036     Document Type: Article

References (34)

1. J. Martel-Pelletier Osteoarthritis Cartilage 7 1999 371
2. M.B. Glodring, and S.R. Glodring J. Cell. Physiol. 213 2007 626
3. M. Fajardo, and P.E. Di Cesare Drugs Aging 22 2005 141
4. G. Singh Surg. Technol. Int. 11 2003 287
5. C. Kiani, L. Chen, Y.J. Wu, A.J. Yee, and B.B. Yang Cell Res. 12 2002 19
6. M.D. Tortorella, T.C. Burn, M.A. Pratta, I. Abbaszade, J.M. Hollis, R. Liu, S.A. Rosenfeld, R.A. Copeland, C.P. Decicco, R. Wynn, A. Rockwell, F. Yang, J.L. Duke, K. Solomon, H. George, R. Bruckner, H. Nagase, Y. Itoh, D.M. Ellis, H. Ross, B.H. Wiswall, K. Murphy, M.C. Hillman, G.F. Hollis, R.C. Newton, R.L. Magolda, J.M. Trzaskos, and E.C. Arner Science 284 1999 1664
7. I. Abbaszade, R.-Q. Liu, F. Yang, S.A. Rosenfeld, H. Ross, J.R. Link, D.M. Ellis, M.D. Tortorella, M.A. Pratta, J.M. Hollis, R. Wynn, J.L. Duke, H.J. George, M.C. Hillman, K. Murphy, B.H. Wiswall, R.A. Copeland, C.P. Decicco, R. Bruckner, H. Nagase, Y. Itoh, R.C. Newton, R.L. Magolda, J.M. Trzaskos, G.F. Hollis, E.C. Arner, and T.C. Burn J. Biol. Chem. 274 1999 23443
8. R.-Q. Liu, and J.M. Trzaskos Curr. Med. Chem. Anti Inflamm. Anti Allergy Agents 4 2005 251
9. F. De Rienzo, P. Saxena, F. Filomia, G. Caselli, F. Colace, L. Stasi, A. Giordani, and M. Menziani Curr. Med. Chem. 16 2009 2395
10. S.S. Glasson, R. Askew, B. Sheppard, B. Carito, T. Blanchet, H.-L. Ma, C.R. Flannery, D. Peluso, K. Kanki, Z. Yang, M.K. Majumdar, and E.A. Morris Nature 434 2005 644
11. H. Stanton, F.M. Rogerson, C.J. East, S.B. Golub, K.E. Lawlor, C.T. Meeker, C.B. Little, K. Last, P.J. Farmer, I.K. Campbell, A.M. Fourie, and A.J. Fosang Nature 434 2005 648
12. H.F. Bigg, and A.D. Rowan Curr. Opin. Pharmacol. 1 2001 314
13. P.D. Brown Expert Opin. Invest. Drugs 9 2000 2167
14. R. Westwood, R.C. Scott, R.L. Somers, M. Coulson, and R.A. Maciewicz Toxicol. Pathol. 37 2009 860
15. M.A. Pratta, W. Yao, C. Decicco, M.D. Tortorella, R.-Q. Liu, R.A. Copeland, R. Magolda, R.C. Newton, J.M. Trzaskos, and E.C. Arner J. Biol. Chem. 46 2003 45539
16. For a recent review of Aggrecanase inhibitors see: A.M. Gilbert, J.A. Bikker, and S.V. O'Neil Expert Opin. Ther. Patents 21 2011 1
17. Barlaam, B. C.; Dowell, R. I.; Finlay, M. R. V.; Newcombe, N.; Tucker, H.; Waterson, D. WO 01/062742, 2001; Chem. Abstr. 2001, 135, 211053.
18. 50 value for the inhibitor was calculated by plotting the raw data in a dose response curve fitting application (e.g., Origin).
19. 2 (Bachem) was used. Similar protocols were applied for measuring the activity of ADAM-17 and ADAM-10 using the substrate Dimethoxyfluorescein-Ser-Pro-Leu-Ala-Gln-Ala-Val-Arg-ser- Ser-Arg-Cys-fluorescein (Bachem).
20. S. Zhou, C.S. Yung, G.B. Cher, E. Chan, W. Duan, M. Huang, and H.L. McLeod Clin. Pharmacokinet. 44 2005 279
21. P.A. Williams, J. Cosme, D.M. Vinkovic, A. Ward, H.C. Angove, P.J. Day, C. Vonrhein, I.J. Tickle, and H. Jhoti Science 305 2004 683
22. S. Gerhardt, G. Hassall, P. Hawtin, E. McCall, L. Flavell, C. Minshull, D. Hargreaves, A. Ting, R.A. Pauptit, A.E. Parker, and W.M. Abbott J. Mol. Biol. 373 2007 891
23. The X-ray crystal ligand-protein structures of both compounds 4 (PDB ID = 3Q2G) and 8f (PDB ID = 3Q2H) have been deposited into the RCSB Protein data bank (http://www.pdb.org/pdb/home/home.do ).
24. M.C. Noe, V. Natarajan, S.L. Snow, P.G. Mitchell, L.L. Lopresti-Morrow, L.M. Reeves, S.A. Yocum, T.J. Carty, J.T. Barberia, F.J. Sweeney, J.L. Liras, M. Vaughn, J. Hardink, J.M. Hawkins, and C. Tokar Bioorg. Med. Chem. Lett. 15 2005 2808
25. M.C. Noe, V. Natarajan, S.L. Snow, L.A. Wolf-Gouveia, P.G. Mitchell, L. Lopresti-Morrow, L.M. Reeves, S.A. Yocum, T.J. Carty, I. Otterness, M.A. Bliven, T.J. Carty, J.T. Barberia, F.J. Sweeney, J.L. Liras, and M. Vaughn Bioorg. Med. Chem. Lett. 15 2005 3385
26. Male and female Han Wistar rats and Beagle dogs were obtained from in-house colonies. Doses administered by the iv route were delivered to rats as a solution in 40% aq dimethylamide (2 mg/kg) and to dogs in 5% DMSO/95% Sorensen's buffer, pH5.5 (1 mg/kg), while those administered by the oral route were delivered to rats in 10% DMSO/90% aq hydroxypropyl methylcellulose/Tween and to dogs in 5% DMSO/95% aq hydroxypropyl methylcellulose/Tween. Blood samples (50-200 μL) were collected from the tail vein of rats (t = 5, 20 and 40 min, 1.5, 3, 6, 12, and 24 h and 15 and 30 min, 1, 2, 3, 6, 12 and 24 h following iv and oral administration, respectively) and the jugular vein of dogs (t = 5, 10, 20 and 40 min, 1, 2, 4, 6, 12, 24, 36 and 48 h and 10, 20 and 40 min, 1, 2, 3, 4, 6, 12, 24, 36 and 48 h following iv and oral administration, respectively). Blood was diluted with an equal volume of water and a 50 μL aliquot of the diluted sample was extracted by precipitation with 150 μL ice-cold acetonitrile. Drug levels were determined by LC-MS/MS analysis. Pharmacokinetic parameters were calculated using the non-compartmental method in Win-Nonlin v2.1 (Pharsight, Mountain View, CA).
27. 50 value for the inhibitor was calculated by plotting the raw data in a dose response curve fitting application (e.g., Origin).
28. Human knee cartilage was obtained at the time of knee replacement surgery or from cadavers. Cartilage was placed in culture and stimulated for 5 days with IL-1 plus Oncostatin M. Aggrecanase activity was measured as for the bovine cultures and a good correlation between the human and bovine systems has been established.
29. A. Dunaiskis, T. Staigers, T. Keltonic, T. Chappie, C. Meltz, R. Dugger, and M.A. Sanner Org. Prep. Proc. Int. 27 1995 600
30. F. Jin, and P.N. Confalone Tetrahedron Lett. 41 2000 3271
31. + 183.
32. + 287.
33. 2O: C, 53.3; H, 6.8; N, 13.5; F, 3.7; S, 6.2. Found: C, 53.6; H, 6.7; N, 3.8; F, 3.8; S, 6.2.
34. J.B. Houston, and D.J. Carlile Drug Metab. Rev. 29 1997 891