Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 11, 2011, Pages 3301-3306

  De Savi, Chris ^a   Pape, Andrew ^a   Sawyer, Yvonne ^a   Milne, David ^a   Davies, Chris ^a   Cumming, John G ^a   Ting, Attilla ^a   Lamont, Scott ^a   Smith, Peter D ^a   Tart, Jonathon ^a   Page, Ken ^a   Moore, Peter ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

ADAM TS4; ADAM TS5; Aggrecanase; Osteoarthritis; Reverse hydroxamate

Indexed keywords

2 CYCLOPROPYL 4 METHYLSULFONYLPHENYL; 2 METHYL 3 PYRIDYL; 2 METHYL 4 METHYLSULFONYL PHENYL; 2 METHYLPHENYL; 2,5 DIMETHYL 3 PYRIDYL; 2,5 DIMETHYL 4 PYRIDYL; 3 METHYL 2 PYRIDYL; 3,5 DIMETHYLISOTHIAZOL 4 YL; 3,5 DIMETHYLISOXAZOL 4 YL; 4 CHLORO 2 METHYL PHENYL; 4 FLUORO 2 METHYL PHENYL; 4 METHYL 3 PYRIDYL; 4,6 DIMETHYL 3 PYRIDYL; AGGRECANASE 1; AGGRECANASE 2; METALLOPROTEINASE INHIBITOR; N HYDROXYFORMAMIDE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; IC 50; MOUSE; NONHUMAN; OSTEOARTHRITIS; STRUCTURE ACTIVITY RELATION; SYSTEMATIC REVIEW;

ADAM PROTEINS; ADMINISTRATION, ORAL; ANIMALS; ENZYME INHIBITORS; FORMAMIDES; HUMANS; MOLECULAR STRUCTURE; OSTEOARTHRITIS; PROCOLLAGEN N-ENDOPEPTIDASE; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SWINE;

EID: 79956096421     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.04.028     Document Type: Article

References (25)

1. C.G. Helmick, D.T. Felson, R.C. Lawrence, S. Gabriel, R. Hirsch, C. Kent Kwoh, M.H. Liang, H. Maradit Kremers, M.D. Mayes, P.A. Merkel, S.R. Pillemer, J.D. Reveille, and J.H. Stone Arthritis Rheum. 58 2008 15
2. Symmons, D. P.; Mathers, C. D.; Pfleger, B. The Global Burden of Osteoarthritis in the Year 2000, GBD 2000 Working Paper, World Health Organisation, Geneva, http://www.who.int/healthinfo/statistics/bod- osteoarthritis.pdf.
3. The American College of Gastroenterology (ACG). Understanding Ulcers, NSAIDs and GI Bleeding. http://www.acg.gi.org/patients/gibleeding/index. asp#compl. Accessed March 2011.
4. M. Fajardo, and P.E. Di Cesare Drugs Aging 22 2005 141
5. G. Singh Surg. Technol. Int. 11 2003 287
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. F. De Rienzo, P. Saxena, F. Filomia, G. Caselli, F. Colace, L. Stasi, A. Giordani, and M. Menziani Curr. Med. Chem. 16 2009 2395
9. A.M. Gilbert, J.A. Bikker, and S.V. O'Neil Expert Opin. Ther. Patents 21 2011 1
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. C. De Savi, A. Pape, J.G. Cumming, A. Ting, P.D. Smith, J.N. Burrows, M. Mills, C. Davies, S. Lamont, D. Milne, C. Cook, P. Moore, Y. Sawyer, and S. Gerhardt Bioorg. Med. Chem. Lett. 21 2011 1376
13. M. Edmonds, and A. Abell T. Takeda, Modern Carbonyl Olefination 1 2004 Wiley-VCH Weinheim, Germany 1 17
14. S. Brock, D.R.J. Hose, J.D. Moseley, A.J. Parker, I. Patel, and A.J. Williams Org. Process Res. Dev. 12 2008 496
15. A.G. Leach, H.D. Jones, D.A. Cosgrove, P.W. Kenny, L. Ruston, P. MacFaul, J.M. Wood, N. Colclough, and B. Law J. Med. Chem. 49 2006 6672
16. J.B. Houston, and D.J. Carlile Drug Metab. Rev. 29 1997 891
17. In house available cyclic ketones were prioritised for synthesis based on modelling (e.g., 14c, 14d, 14f, 14g, 14i and 14j). The conformations of models were generated with Omega licensed from Openeye (http://www.eyesopen.com/ ) and corrected poor torsions with in house X-ray or CSD crystal structure information when appropriate. The models were then docked using Glide into ADAM-TS1 structure (PDB ID = 3Q2H) and overlaid with compound 1 in Maestro. Glide and Maestro were licensed from Schrödinger, LGG (www.schrodinger.com ).
18. M.H. Bridgland-Taylor, A.C. Hargreaves, A. Easter, A. Orme, A. Harmer, D.C. Henthorn, M. Ding, A. Davis, B.G. Small, C.G. Heapy, N. Abi-Gerges, F. Paulsson, I. Jacobson, K. Schroeder, B. Neagle, N. Albertson, T.G. Hammond, M. Sullivan, E. Sullivan, J.-P. Valentin, and C.E. Pollard J. Pharmacol. Toxicol. Methods 54 2006 189
19. D. McGinnity, J. Collington, R. Austin, and R. Riley Curr. Drug Metab. 8 2007 463
20. M. Waring Bioorg. Med. Chem. Lett. 19 2009 2844
21. T.J. Ritchie, and S.J.F. MacDonald Drug Discovery Today 14 2009 1011
22. F. Lovering, J. Bikker, and C. Humblet J. Med. Chem. 52 2009 6752
23. 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
24. M. Reijman, J.M.W. Hazes, S.M.A. Bierma-Zeinstra, B.W. Koes, S. Christgau, C. Christiansen, A.G. Uitterlinden, and H.A.P. Pols Arthritis Rheum. 50 2004 2471
25. P.A. Jimenez, S.S. Glasson, O.V. Trubetskoy, and H.B. Haimes Lab. Anim. Sci. 47 1997 598