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169 a.a.
_CA
_ZN
Key reference
DOI no: 10.1021/jm000246e J Med Chem 43:4948-4963 (2000) PubMed id: 11150165
Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines. M.G.Natchus, R.G.Bookland, B.De, N.G.Almstead, S.Pikul, M.J.Janusz, S.A.Heitmeyer, E.B.Hookfin, L.C.Hsieh, M.E.Dowty, C.R.Dietsch, V.S.Patel, S.M.Garver, F.Gu, M.E.Pokross, G.E.Mieling, T.R.Baker, D.J.Foltz, S.X.Peng, D.M.Bornes, M.J.Strojnowski, Y.O.Taiwo. ABSTRACT
A series of hydroxamates was prepared from an aminoproline scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors, such as compound 47, display broad-spectrum activity with sub-nanomolar potency for some enzymes. Modifications of the P1' portion of the molecule played a key role in affecting both potency and selectivity within the MMP family. Longer-chain aliphatic substituents in this region of the molecule tended to increase potency for MMP-3 and decrease potency for MMP-1, as exemplified by compounds 48-50, while aromatic substituents, as in compound 52, generated broad-spectrum inhibition. The data is rationalized based upon X-ray crystal data which is also presented. While the in vitro peroral absorption seemed to be less predictable, it tended to decrease with longer and more hydrophilic substituents. Finally, a rat model of osteoarthritis was used to evaluate the efficacy of these compounds, and a direct link was established between their pharmacokinetics and their in vivo efficacy.
Literature references that cite this PDB file's key reference
PubMed id Reference
19565489 V.M.Baragi, G.Becher, A.M.Bendele, R.Biesinger, H.Bluhm, J.Boer, H.Deng, R.Dodd, M.Essers, T.Feuerstein, B.M.Gallagher, C.Gege, M.Hochgürtel, M.Hofmann, A.Jaworski, L.Jin, A.Kiely, B.Korniski, H.Kroth, D.Nix, B.Nolte, D.Piecha, T.S.Powers, F.Richter, M.Schneider, C.Steeneck, I.Sucholeiki, A.Taveras, A.Timmermann, J.Van Veldhuizen, J.Weik, X.Wu, and B.Xia (2009).
A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models.Arthritis Rheum, 60, 2008-2018.
15526325 M.Kontoyianni, G.S.Sokol, and L.M.McClellan (2005).
Evaluation of library ranking efficacy in virtual screening.J Comput Chem, 26, 11-22.
15999201 S.R.Wallner, B.M.Nestl, and K.Faber (2005).
Highly enantioselective stereo-inverting sec-alkylsulfatase activity of hyperthermophilic Archaea.Org Biomol Chem, 3, 2652-2656.
14732707 V.Lukacova, Y.Zhang, M.Mackov, P.Baricic, S.Raha, J.A.Calvo, and S.Balaz (2004).
Similarity of binding sites of human matrix metalloproteinases.J Biol Chem, 279, 14194-14200.
12515831 S.Wei, Y.Chen, L.Chung, H.Nagase, and K.Brew (2003).
Protein engineering of the tissue inhibitor of metalloproteinase 1 (TIMP-1) inhibitory domain. In search of selective matrix metalloproteinase inhibitors.J Biol Chem, 278, 9831-9834. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.
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