Skip to main content

Hydroxamic Acids as Matrix Metalloproteinase Inhibitors

  • Chapter
  • First Online:
Book cover Matrix Metalloproteinase Inhibitors

Part of the book series: Experientia Supplementum ((EXS,volume 103))

Abstract

Matrix metalloproteinases (MMPs), an increasing family of zinc- and calcium-dependent endopeptidases, are involved in both the tissue remodeling and the degradation of extracellular matrix (ECM). These enzymes have been a pharmaceutical target for over 25 years in order to develop many families of therapeutically important synthetic matrix metalloproteinase inhibitors (MMPIs) for the treatment of several serious pathologies. Although clinical trials on most of the MMPIs gave disappointing results, at least one MMPI (Periostat™) has been approved by the FDA for the treatment of periodontal disease. Current research efforts on the development of selective inhibitors toward certain MMPs gave a vast number of small molecules as potent MMPIs, of which, some of the effective candidates are in their various stages of (pre)clinical trials for the treatment of various diseases such as arthritis and different cancers. The selectivity of MMPIs toward specific MMPs depends mainly on their structural templates or scaffolds and the variations in their substituents. Thus, the combination of traditional, mechanism-based, and structural-based approaches may help for the future development of specific MMPIs. In recent years, research focuses on the design and development of MMPIs possess a hydroxamic acid moiety, a strong Zn(II)-binding group, which leads to their high-affinity binding to the enzymic sites of the MMPs. We herein discuss the hydroxamic acid-based MMPIs with respect to their mechanism of interaction, structure–activity relationship (SAR), quantitative structure–activity relationship (QSAR), recent development, and clinical trials.

Keywords

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADME:

Absorption distribution, metabolism, and excretion

CoMFA:

Comparative molecular field analysis

CoMSIA:

Comparative molecular similarity indices analysis

ECM:

Extracellular matrix

HBA:

Hydrogen-bond acceptor

HBD:

Hydrogen-bond donor

MMPs:

Matrix metalloproteinases

MMPIs:

Matrix metalloproteinase inhibitors

QSAR:

Quantitative structure–activity relationship

2D-QSAR:

Two-dimensional QSAR (classical QSAR)

3D-QSAR:

Three-dimensional QSAR

SAR:

Structure–activity relationship

TACE:

TNF-α converting enzyme

TIMMPs:

Tissue inhibitors of MMPs

ZBG:

Zinc-binding group

References

  • Amin EA, Welsh WJ (2001) Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a novel class of piperazine-based stromelysin-1 (MMP-3) inhibitors: applying a “divide and conquer” strategy. J Med Chem 44:3849–3855

    CAS  Google Scholar 

  • Amin EA, Welsh WJ (2006) Highly predictive CoMFA and CoMSIA models for two series of stromelysin-1 (MMP-3) inhibitors elucidate S1′ and S1-S2′ binding modes. J Chem Inf Model 46:1775–1783

    CAS  PubMed  Google Scholar 

  • Aranapakam V, Davis JM, Grosu GT, Baker J, Ellingboe J, Zask A, Levin JI, Sandanayaka VP, Du M, Skotnicki JS, DiJoseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling R, Tillett J, Zhao W, McDevitt J, Xu ZB (2003) Synthesis and structure-activity relationship of N-substituted 4-arylsulfonylpiperidine-4-hydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J Med Chem 46:2376–2396

    CAS  PubMed  Google Scholar 

  • Armando R, Elisa N, Tiziano T, Elisabetta O (2010) Arylsulfonamide derivatives, especially dimeric hydroxamic acid-containing amino acids, metalloproteases inhibitors and their preparation, pharmaceutical compositions and use in the treatment of degenerative disorders. Eur Pat Appl EP 2149568 A1 20100203

    Google Scholar 

  • Attolino E, Calderone V, Dragoni E, Fragai M, Richichi B, Luchinat C, Cristina Nativi C (2010) Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs). Eur J Med Chem 45:5919–5925

    CAS  PubMed  Google Scholar 

  • Barta TE, Becker DP, Bedell LJ, De Crescenzo GA, McDonald JJ, Mehta P, Munie GE, Villamil CI (2001) Selective, orally active MMP inhibitors with an aryl backbone. Bioorg Med Chem Lett 11:2481–2483

    CAS  PubMed  Google Scholar 

  • Barta TE, Becker DP, Bedell LJ, De Crescenzo GA, McDonald JJ, Munie GE, Rao S, Shieh HS, Stegeman R, Stevens AM, Villamil CI (2000) Synthesis and activity of selective MMP inhibitors with an aryl backbone. Bioorg Med Chem Lett 10:2815–2817

    CAS  PubMed  Google Scholar 

  • Bauer L, Exner O (1974) The chemistry of hydroxamic acids and N-hydroxyimides. Angew Chem Int Ed Engl 13:376–384

    Google Scholar 

  • Becker DP, Barta TE, Bedell LJ, Boehm TL, Bond BR, Carroll J, Carron CP, DeCrescenzo GA, Easton AM, Freskos JN, Funckes-Shippy CL, Heron M, Hockerman S, Howard PC, Kiefer JR, Li MH, Mathis KJ, McDonald JJ, Mehta PP, Munie GE, Sunyer T, Swearingen CA, Villamil CI, Welsch D, Williams JM, Yu Y, Yao J (2010) Orally active MMP-1 sparing α-tetrahydropyranyl and α-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis, and cardiovascular disease. J Med Chem 53:6653–6680

    CAS  PubMed  Google Scholar 

  • Bourguet E, Sapi J, Emonard H, Hornebeck W (2009) Control of melanoma invasiveness by anticollagenolytic agents: a reappraisal of an old concept. Anticancer Agents Med Chem 9:576–597

    CAS  PubMed  Google Scholar 

  • Brinckerhoff CE, Matrisian LM (2002) Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 3:207–214

    CAS  PubMed  Google Scholar 

  • Brown S, Meroueh SO, Fridman R, Mobashery S (2004) Quest for selectivity in inhibition of matrix metalloproteinases. Curr Top Med Chem 4:1227–1238

    CAS  PubMed  Google Scholar 

  • Browner MF, Smith WW, Castelhano AL (1995) Matrilysin-inhibitor complex: common among metalloproteases. Biochemistry 34:6602–6610

    CAS  PubMed  Google Scholar 

  • Burns DM, He C, Li Y, Scherle P, Liu X, Marando CA, Covington MB, Yang G, Pan M, Turner S, Fridman JS, Hollis G, Vaddi K, Yeleswaram S, Newton R, Friedman S, Metcalf B, Yaoa W (2008) Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1′ permutations. Bioorg Med Chem Lett 18:560–564

    CAS  PubMed  Google Scholar 

  • Burns DM, Li YL, Shi E, He C, Xu M, Zhuo J, Zhang C, Qian DQ, Li Y, Wynn R, Covington MB, Katiyar K, Marando CA, Fridman JS, Scherle P, Friedman S, Metcalf B, Yao W (2009) Compelling P1 substituent affect on metalloprotease binding profile enables the design of a novel cyclohexyl core scaffold with excellent MMP selectivity and HER-2 sheddase inhibition. Bioorg Med Chem Lett 19:3525–3530

    CAS  PubMed  Google Scholar 

  • Burzlaff N (2006) Model complexes for zinc-containing enzymes. In: Douglas B, McDaniel DH, Alexander JJ (eds) Concepts and models in bioinorganic chemistry, vol 17. Wiley, New York, pp 397–429

    Google Scholar 

  • Campestre C, Tortorella P, Agamennone M, Preziuso S, Biasone A, Nuti E, Rossello A, Carlo Gallina C (2008) Peptidyl 3-substituted 1-hydroxyureas as isosteric analogues of succinylhydroxamate MMP inhibitors. Eur J Med Chem 43:1008–1014

    CAS  PubMed  Google Scholar 

  • Cheng M, De B, Pikul S, Almstead NG, Natchus MG, Anastasio MV, McPhail SJ, Snider CE, Taiwo YO, Chen L, Dunaway CM, Gu F, Dowty ME, Mieling GE, Janusz MJ, Wang-Weigand S (2000) Design and synthesis of piperazine based matrix metalloproteinase inhibitors. J Med Chem 43:369–380

    CAS  PubMed  Google Scholar 

  • Cheng XC, Wang Q, Fang H, Tang W, Xu WF (2008a) Design, synthesis and preliminary evaluation of novel pyrrolidine derivatives as matrix metalloproteinase inhibitors. Eur J Med Chem 43:2130–2139

    CAS  PubMed  Google Scholar 

  • Cheng XC, Wang Q, Fang H, Xu WF (2008b) Role of sulfonamide group in matrix metalloproteinase inhibitors. Curr Med Chem 15:368–373

    CAS  PubMed  Google Scholar 

  • Chun K, Park SK, Kim HM, Choi Y, Kim MH, Park CH, Joe BY, Chun TG, Choi HM, Lee HY, Hong SH, Kim MS, Nam KY, Han G (2008) Chromen-based TNF-α converting enzyme (TACE) inhibitors: design, synthesis, and biological evaluation. Bioorg Med Chem 16:530–535

    CAS  PubMed  Google Scholar 

  • Condon JS, Joseph-McCarthy D, Levin JI, Lombart HG, Lovering FE, Sun L, Wang W, Xua W, Zhang Y (2007) Identification of potent and selective TACE inhibitors via the S1 pocket. Bioorg Med Chem Lett 17:34–39

    CAS  PubMed  Google Scholar 

  • Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295:2387–2392

    CAS  PubMed  Google Scholar 

  • Cramer RD III, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967

    CAS  PubMed  Google Scholar 

  • Cross JB, Duca JS, Kaminski JJ, Madison VS (2002) The active site of a zinc dependent metalloproteinase influences the computed pKa of ligands coordinated to the catalytic zinc ion. J Am Chem Soc 124:11004–11007

    CAS  PubMed  Google Scholar 

  • Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174

    CAS  PubMed  Google Scholar 

  • Eriksson L, Jaworska J, Worth AP, Cronin MTD, McDowell RM, Gramatica P (2003) Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs. Environ Health Perspect 111:1361–1375

    CAS  PubMed  Google Scholar 

  • Faust A, Waschkau B, Waldeck J, Höltke C, Breyholz HJ, Wagner S, Kopka K, Schober O, Heindel W, Schäfers M, Bremer C (2009) Synthesis and evaluation of a novel hydroxamate based fluorescent photoprobe for imaging of matrix metalloproteinases. Bioconjugate Chem 20:904–912

    CAS  Google Scholar 

  • Fingleton B (2007) Matrix metalloproteinases as valid clinical targets. Curr Pharm Des 13:333–346

    CAS  PubMed  Google Scholar 

  • Fisher JF, Mobashery S (2006) Recent advances in MMP inhibitor design. Cancer Metastasis Rev 25:115–136

    CAS  PubMed  Google Scholar 

  • Fray MJ, Burslem MF, Dickinson RP (2001) Selectivity of inhibition of matrx metalloproteases MMP-3 and MMP-2 by succinyl hydroxamares and their carboxylic acid analogues is dependent on P3′ group chirality. Bioorg Med Chem Lett 11:567–570

    CAS  PubMed  Google Scholar 

  • Fray MJ, Dickinson RP (2001) Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1). Bioorg Med Chem Lett 11:571–574

    CAS  PubMed  Google Scholar 

  • Ganea E, Trifan M, Laslo AC, Putina G, Cristescu C (2007) Matrix metalloproteinases: useful and deleterious. Biochem Soc Trans 35:689–691

    CAS  PubMed  Google Scholar 

  • Gedeck P, Lewis RA (2008) Exploiting QSAR models in lead optimization. Curr Opin Drug Discov Dev 11:569–575

    CAS  Google Scholar 

  • Geurink PP, Klein T, Prèly L, Paal K, Leeuwenburgh MA, van der Marel GA, Kauffman HF, Overkleeft HS, Bischoff R (2010) Design of peptide hydroxamate-based photoreactive activity-based probes of zinc-dependent metalloproteases. Eur J Org Chem 2010:2100–2112

    Google Scholar 

  • Grams F, Crimmin M, Hinnes L, Huxley P, Pieper M, Tschesche H, Bode W (1995a) Structure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor. Biochemistry 34:14012–14020

    CAS  PubMed  Google Scholar 

  • Grams F, Reinemer P, Powers JC, Kleine T, Pieper M, Tschesche H, Huber R, Bode W (1995b) X-ray structures of human neutrophil collagenase complexed with hydroxamate and peptide thiols inhibitors. Implications for substrate binding and rational drug design. Eur J Biochem 228:830–841

    CAS  PubMed  Google Scholar 

  • Gowravaram MR, Tomczuk BE, Johnson JS, Delecki D, Cook ER, Ghose AK, Mathiowetz AM, Spurlino JC, Rubin B, Smith DL, Pulvino T, Wahl RC (1995) Inhibition of matrix metalloproteinases by hydroxamates containing heteroatom-based modifications of the P1′ group. J Med Chem 38:2570–2581

    CAS  PubMed  Google Scholar 

  • Gupta SP (2007) Quantitative structure-activity relationship studies on zinc-containing metalloproteinase inhibitors. Chem Rev 107:3042–3087

    CAS  PubMed  Google Scholar 

  • Gupta SP, Bagaria P, Kumar Satuluri VSA (2008) A quantitative structure-activity relationship study on a novel series of hydroxamic acid analogs acting as matrix metalloproteinase inhibitors. Lett Drug Des Discov 5:281–285

    CAS  Google Scholar 

  • Gupta SP, Kumaran S (2005a) A quantitative structure–activity relationship study on some series of anthranilic acid-based matrix metalloproteinase inhibitors. Bioorg Med Chem 13:5454–5462

    CAS  PubMed  Google Scholar 

  • Gupta SP, Kumaran S (2005b) Quantitative structure-activity relationship studies on matrix metalloproteinase inhibitors: bicyclic heteroaryl hydroxamic acid analogs. Lett Drug Des Discov 2:522–528

    CAS  Google Scholar 

  • Gupta SP, Kumaran S (2006a) Quantitative structure-activity relationship studies on matrix metalloproteinase inhibitors: hydroxamic acid analogs. Med Chem 2:243–250

    CAS  PubMed  Google Scholar 

  • Gupta SP, Kumaran S (2006b) Quantitative structure-activity relationship studies on matrix metalloproteinase inhibitors: piperazine, piperidine and diazepine hydroxamic acid analogs. Asian J Biochem 1:211–223

    CAS  Google Scholar 

  • Gupta SP, Maheswaran B, Pande V, Kumar D (2003) A comparative QSAR study on carbonic anhydrase and matrix metalloproteinase inhibition by sulfonylated amino acid hydroxamates. J Enzyme Inhib Med Chem 18:7–13

    CAS  PubMed  Google Scholar 

  • Hansch C, Hoekman D, Leo A, Weininger D, Selassie CD (2002) Chem-Bioinformatics. Comparative QSAR at the interface between chemistry and biology. Chem Rev 102:783–812

    CAS  PubMed  Google Scholar 

  • Hansch C, Maloney PP, Fujita T, Muir RM (1962) Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients. Nature 194:178–180

    CAS  Google Scholar 

  • Holms J, Mast K, Marcotte P, Elmore I, Li J, Pease L, Glaser K, Morgan D, Michaelides M, Davidsen S (2001) Discovery of selective hydroxamic acid inhibitors of tumor necrosis factor-α converting enzyme. Bioorg Med Chem Lett 11:2907–2910

    CAS  PubMed  Google Scholar 

  • Hu J, Van den Steen PE, Sang QXA, Opdenakker G (2007) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 6:480–498

    CAS  PubMed  Google Scholar 

  • Huang A, Joseph-McCarthy D, Lovering F, Sun L, Wang W, Xu W, Zhu Y, Cui J, Zhang Y, Levin JI (2007) Structure-based design of TACE selective inhibitors: manipulations in the S10–S30 pocket. Bioorg Med Chem 15:6170–6181

    CAS  PubMed  Google Scholar 

  • Klebe G (1998) Comparative molecular similarity indices analysis. CoMSIA. Perspect Drug Discov Des 12/13/14 (3D QSAR in Drug Design: Recent Advances): 87–104

    Google Scholar 

  • Kolodziej SA, Hockerman SL, Boehm TL, Carroll JN, DeCrescenzo GA, McDonald JJ, Mischke DA, Munie GE, Fletcher TR, Rico JG, Stehle NW, Swearingen C, Becker DP (2010a) Orally bioavailable dual MMP-1/MMP-14 sparing, MMP-13 selective α-sulfone hydroxamates. Bioorg Med Chem Lett 20:3557–3560

    CAS  PubMed  Google Scholar 

  • Kolodziej SA, Hockerman SL, DeCrescenzo GA, McDonald JJ, Mischke DA, Munie GE, Fletcher TR, Stehle N, Swearingen C, Becker DP (2010b) MMP-13 selective isonipecotamide α-sulfone hydroxamates. Bioorg Med Chem Lett 20:3561–3564

    CAS  PubMed  Google Scholar 

  • Kumaran S, Gupta SP (2007) A quantitative structure-activity relationship study on matrix metalloproteinase inhibitors: piperidine sulfonamide aryl hydroxamic acid analogs. J Enzyme Inhib Med Chem 22:23–27

    CAS  PubMed  Google Scholar 

  • Lee MS, Izobe M, Imaida K, Wang CY, Aoki K (1991) Carcinogenic potential and metabolic activation of 2-naphthohydroxamic acid in S. typhimurium TA91. Prog Pharm Clin Pharm 8:275–288

    CAS  Google Scholar 

  • Levin JI, Chen JM, Cheung K, Cole D, Crago C, Santos ED, Du X, Khafizova G, MacEwan G, Niu C, Salaski EJ, Zask A, Cummons T, Sung A, Xu J, Zhang Y, Xu W, Ayral-Kaloustian S, Jin G, Cowling R, Barone D, Mohler KM, Black RA, Skotnicki JS (2003) Acetylenic TACE inhibitors. Part 1. SAR of the acyclic sulfonamide hydroxamates. Bioorg Med Chem Lett 13:2799–2803

    CAS  PubMed  Google Scholar 

  • Levin JI, Chen J, Du M, Hogan M, Kincaid S, Nelson FC, Venkatesan AM, Wehr T, Zask A, DiJoseph J, Killar LM, Skala S, Sung A, Sharr M, Roth C, Jin G, Cowling R, Mohler KM, Black RA, March CJ, Skotnicki JS (2001a) The discovery of anthranilic acid-based MMP inhibitors. Part 2: SAR of the 5-position and P11 groups. Bioorg Med Chem Lett 11:2189–2192

    CAS  PubMed  Google Scholar 

  • Levin JI, DiJoseph JF, Killar LM, Sung A, Walter T, Sharr MA, Roth CE, Skotnicki JS, Albright JD (1998) The synthesis and biological activity of a novel series of diazepine MMP inhibitors. Bioorg Med Chem Lett 8:2657–2662

    CAS  PubMed  Google Scholar 

  • Levin JI, Du MT, DiJoseph JF, Killar LM, Sung A, Walter T, Sharr MA, Roth CE, Moy FJ, Powers R, Jin G, Cowling R, Skotnicki JS (2001b) The discovery of anthranilic acid-based MMP inhibitors. Part 1: SAR of the 3-position. Bioorg Med Chem Lett 11:235–238

    CAS  PubMed  Google Scholar 

  • Li YL, Shi E, Burns D, Li Y, Covington MB, Pan M, Scherle P, Friedman S, Metcalf B, Yao W (2009) Discovery of novel selective HER-2 sheddase inhibitors through optimization of P1 moiety. Bioorg Med Chem Lett 19:5037–5042

    CAS  PubMed  Google Scholar 

  • Lu Z, Ott GR, Anand R, Liu RQ, Covington MB, Vaddi K, Qian M, Newton RC, Christ DD, Trzaskos J, Duan JJW (2008) Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-a converting enzyme (TACE): discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1′ substituents. Bioorg Med Chem Lett 18:1958–1962

    CAS  PubMed  Google Scholar 

  • MacPherson LJ, Bayburt EK, Capparelli MP, Carroll BJ, Goldstein R, Justice MR, Zhu L, Hu S-I, Melton RA, Fryer L, Goldberg RL, Doughty JR, Spirito S, Blancuzzi V, Wilson D, O’Byrne EM, Ganu V, Parker DT (1997) Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J Med Chem 40:2525–2532

    CAS  PubMed  Google Scholar 

  • Marques SM, Nuti E, Rossello A, Supuran CT, Tuccinardi T, Martinelli A, Santos A (2008) Dual inhibitors of matrix metalloproteinases and carbonic anhydrases: iminodiacetyl-based hydroxamate-benzenesulfonamide conjugates. J Med Chem 51:7968–7979

    CAS  PubMed  Google Scholar 

  • Martin MF, Beckett RP, Bellamy CL, Courtney PF, Davies SJ, Drummond AH, Dodd R, Pratt LM, Patel SR, Ricketts ML, Todd RS, Tuffnell AR, Ward JWS, Whittaker M (1999) The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors. Bioorg Med Chem Lett 9:2887–2892

    CAS  PubMed  Google Scholar 

  • Mekapati SB, Kurup A, Verma RP, Hansch C (2005) The role of hydrophobic properties of chemicals in promoting allosteric reactions. Bioorg Med Chem 13:3737–3762

    CAS  PubMed  Google Scholar 

  • Moroy G, Denhez C, Mourabit HE, Toribio A, Dassonville A, Decarme M, Renault JH, Mirand C, Bellon G, Sapi J, Alix AJP, Hornebeck W, Bourguet E (2007) Simultaneous presence of unsaturation and long alkyl chain at P’1 of Ilomastat confers selectivity for gelatinase A (MMP-2) over gelatinase B (MMP-9) inhibition as shown by molecular modelling studies. Bioorg Med Chem 15:4753–4766

    CAS  PubMed  Google Scholar 

  • Nicolotti O, Miscioscia TF, Leonetti F, Muncipinto G, Carotti A (2007) Screening of matrix metalloproteinases available from the protein data bank: insights into biological functions, domain organization, and zinc binding groups. J Chem Inf Model 47:2439–2448

    CAS  PubMed  Google Scholar 

  • Noe MC, Natarajan V, Snow SL, Wolf-Gouveia LA, Mitchell PG, Lopresti-Morrow L, Reeves LM, Yocum SA, Otterness I, Bliven MA, Carty TJ, Barberia JT, Sweeney FJ, Liras JL, Vaughn M (2005) Discovery of 3-OH-3- methylpipecolic methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13. Bioorg Med Chem Lett 15:3385–3388

    CAS  PubMed  Google Scholar 

  • Nuti E, Casalini F, Avramova SI, Santamaria S, Cercignani G, Marinelli L, Pietra VL, Novellino E, Orlandini E, Nencetti S, Tuccinardi T, Martinelli A, Lim NH, Visse R, Nagase H, Rossello A (2009) N-O-Isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis. J Med Chem 52:4757–4773

    CAS  PubMed  Google Scholar 

  • Overall CM, Kleifeld O (2006a) Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer 94:941–946

    CAS  PubMed  Google Scholar 

  • Overall CM, Kleifeld O (2006b) Tumor microenvironments opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 6:227–239

    CAS  PubMed  Google Scholar 

  • Overall CM, López-Otín C (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2:657–672

    CAS  PubMed  Google Scholar 

  • Parks WC, Wilson CL, López-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4:617–629

    CAS  PubMed  Google Scholar 

  • Pikul S, McDow Dunham KL, Almstead NG, De B, Natchus MG, Anastasio MV, McPhail SJ, Snider CE, Taiwo YO, Chen L, Dunaway CM, Gu F, Mieling GE (1999) Design and synthesis of phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases. J Med Chem 42:87–94

    CAS  PubMed  Google Scholar 

  • Pirard B (2007) Insight into the structural determinants for selective inhibition of matrix metalloproteinases. Drug Discov Today 12:640–646

    CAS  PubMed  Google Scholar 

  • Plewe MB, Butler SL, Dress KR, Hu Q, Johnson TW, Kuehler JE, Kuki A, Lam H, Liu W, Nowlin D, Peng Q, Rahavendran SV, Tanis SP, Tran KT, Wang H, Yang A, Zhang J (2009) Azaindole hydroxamic acids are potent HIV-1 integrase inhibitors. J Med Chem 52:7211–7219

    CAS  PubMed  Google Scholar 

  • Raffetto JD, Khalil RA (2008) Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 75:346–359

    CAS  PubMed  Google Scholar 

  • Rao BG (2005) Recent developments in the design of specific matrix metalloproteinase inhibitors aided by structural and computational studies. Curr Pharm Des 11:295–322

    CAS  PubMed  Google Scholar 

  • Ravanti L, Kahari V-M (2000) Matrix metalloproteinases in wound repair. Int J Mol Med 6:391–407

    CAS  PubMed  Google Scholar 

  • Roy K, Pal DK, De AU, Sengupta C (2001) QSAR of matrix metalloproteinase inhibitor N-[(substituted phenyl)sulfonyl]-N-4-nitrobenzyl-glycine hydroxamates using LFER model. Drug Des Discov 17:315–323

    CAS  PubMed  Google Scholar 

  • Scozzafava A, Supuran CT (2000a) Carbonic anhydrase and matrix metalloproteinase inhibitors: sulfonylated amino acid hydroxamates with MMP inhibitory properties act as efficient inhibitors of CA isozymes I, II, and IV, and N-hydroxysulfonamides inhibit both these zinc enzymes. J Med Chem 43:3677–3687

    CAS  PubMed  Google Scholar 

  • Scozzafava A, Supuran CT (2000b) Protease inhibitors: synthesis of potent bacterial collagenase and matrix metalloproteinase inhibitors incorporating N-4-nitrobenzylsulfonylglycine hydroxamate moieties. J Med Chem 43:1858–1865

    CAS  PubMed  Google Scholar 

  • Selassie C, Verma RP (2010) History of quantitative structure–activity relationships. In: Abraham DJ, Rotella DP (eds) Burger’s medicinal chemistry, drug discovery and development, vol 1, 7th edn. Wiley, New York, pp 1–95

    Google Scholar 

  • Skiles JW, Monovich LG, Jeng AY (2000) Matrix metalloproteinase inhibitors for treatment of cancer. Annu Rep Med Chem 35:167–176

    CAS  Google Scholar 

  • Skipper PL, Tannenbaum SR, Thilly WG, Furth EE, Bishop WW (1980) Mutagenicity of hydroxamic acids and probable involvement of carbamoylation. Cancer Res 40:4704–4708

    CAS  PubMed  Google Scholar 

  • Sørensen MD, Blæhr LKA, Christensen MK, Høyer T, Latini S, Hjarnaa PJV, Björkling F (2003) Cyclic phosphinamides and phosphonamides, novel series of potent matrix metalloproteinase inhibitors with antitumour activity. Bioorg Med Chem 11:5461–5484

    PubMed  Google Scholar 

  • Sternlicht M, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516

    CAS  PubMed  Google Scholar 

  • Subramaniam R, Haldar MK, Tobwala S, Ganguly B, Srivastava DK, Mallik S (2008) Novel bis-(arylsulfonamide) hydroxamate-based selective MMP inhibitors. Bioorg Med Chem Lett 18:3333–3337

    CAS  PubMed  Google Scholar 

  • Supuran CT, Scozzafaca A (2002) Matrix metalloproteinases. In: Smith HJ, Simons C (eds) Proteinase and peptidase inhibition: recent potential targets for drug development. Taylor and Francis, London; New York, pp 35–61

    Google Scholar 

  • Tsai KC, Lin TH (2004) A ligand-based molecular modeling study on some matrix metalloproteinase-1 inhibitors using several 3D QSAR techniques. J Chem Inf Comput Sci 44:1857–1871

    CAS  PubMed  Google Scholar 

  • Tua G, Xu W, Huangb H, Lib S (2008) Progress in the development of matrix metalloproteinase inhibitors. Curr Med Chem 15:1388–1395

    Google Scholar 

  • Tuccinardi T, Nuti E, Ortore G, Rossello A, Avramova SI, Martinelli A (2008) Development of a receptoe-based 3D-QSAR study for the analysis of MMP-2, MMP-3, and MMP-9 inhibitors. Bioorg Med Chem 16:7749–7758

    CAS  PubMed  Google Scholar 

  • Venkatesan AM, Davis JM, Grosu GT, Baker J, Zask A, Levin JI, Ellingboe J, Skotnicki JS, DiJoseph JF, Sung A, Jin G, Xu W, McCarthy DJ, Barone D (2004) Synthesis and structure-activity relationships of 4-alkynyloxy phenyl sulfanyl, sulfinyl, and sulfonyl alkyl hydroxamates as tumor necrosis factor-α converting enzyme and matrix metalloproteinase inhibitors. J Med Chem 47:6255–6269

    CAS  PubMed  Google Scholar 

  • Verma RP, Hansch C (2007) Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem 15:2223–2268

    CAS  PubMed  Google Scholar 

  • Verma RP, Hansch C (2009) Camptothecins: a SAR/QSAR Study. Chem Rev 109:213–235

    CAS  PubMed  Google Scholar 

  • Verma RP, Hansch C (2011) Use of 13C NMR chemical shift as QSAR/QSPR descriptor. Chem Rev 111:2865–2899

    CAS  PubMed  Google Scholar 

  • Vincenti MP, Brinckerhoff CE (2002) Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res 4:157–164

    CAS  PubMed  Google Scholar 

  • Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92:827–839

    CAS  PubMed  Google Scholar 

  • von Roedern EG, Grams F, Brandstetter H, Moroder L (1998) Design and synthesis of malonic acid-based inhibitors of human neutrophil collagenase (MMP8). J Med Chem 41:339–345

    Google Scholar 

  • Vu TH, Werb Z (2000) Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 14:2123–2133

    CAS  PubMed  Google Scholar 

  • Wang CY, Linsmaier-Bednar EM, Lee MS (1981) Mutagenicity of the O-esters of N-acylhydroxylamines for salmonella. Chem Biol Interact 34:267–278

    CAS  PubMed  Google Scholar 

  • Wagner S, Breyholz HJ, Law MP, Faust A, Höltke C, Schröer S, Haufe G, Levkau B, Schober O, Schäfers M, Kopka K (2007) Novel fluorinated derivatives of the broad-spectrum MMP inhibitors N-Hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)- and (3-picolyl)-amino]-3-methyl-butanamide as potential tools for the molecular imaging of activated MMPs with PET. J Med Chem 50:5752–5764

    CAS  PubMed  Google Scholar 

  • Whitlock GA, Dack KN, Dickinson RP, Lewis ML (2007) A novel series of highly selective inhibitors of MMP-3. Bioorg Med Chem Lett 17:6750–6753

    CAS  PubMed  Google Scholar 

  • Whittaker M, Floyd CD, Brown P, Gearing AJH (1999) Design and therapeutic application of matrix metalloproteinase inhibitors. Chem Rev 99:2735–2776

    CAS  PubMed  Google Scholar 

  • Xi L, Du J, Li S, Li J, Liu H, Yao X (2010) A combined molecular modeling study on gelatinases and their potent inhibitors. J Comput Chem 31:24–42

    CAS  PubMed  Google Scholar 

  • Yang SM, Scannevin RH, Wang B, Burke SL, Huang Z, Karnachi P, Wilson LJ, Rhodes KJ, Lagu B, Murray WV (2008a) β-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: part 2. Optimization of a-amino substituents. Bioorg Med Chem Lett 18:1140–1145

    CAS  PubMed  Google Scholar 

  • Yang SM, Scannevin RH, Wang B, Burke SL, Wilson LJ, Karnachi P, Rhodes KJ, Lagu B, Murray WV (2008b) β-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: part 1. Design, synthesis, and lead identification. Bioorg Med Chem Lett 18:1135–1139

    CAS  PubMed  Google Scholar 

  • Yao W, Zhuo J, Burns DM, Li YL, Qian DQ, Zhang C, He C, Xu M, Shi E, Li Y, Marando CA, Covington MB, Yang G, Liu X, Pan M, Fridman JS, Scherle P, Wasserman ZR, Hollis G, Vaddi K, Yeleswaram S, Newton R, Friedman S, Metcalf B (2008) Design and identification of selective HER-2 sheddase inhibitors via P1’ manipulation and unconventional P2’ perturbations to induce a molecular metamorphosis. Bioorg Med Chem Lett 18:159–163

    CAS  PubMed  Google Scholar 

  • Yao W, Zhuo J, Burns DM, Xu M, Zhang C, Li YL, Qian DQ, He C, Weng L, Shi E, Lin Q, Agrios C, Burn TC, Caulder E, Covington MB, Fridman JS, Friedman S, Katiyar K, Hollis G, Li Y, Liu C, Liu X, Marando CA, Newton R, Pan M, Scherle P, Taylor N, Vaddi K, Wasserman ZR, Wynn R, Yeleswaram S, Jalluri R, Bower M, Zhou BB, Metcalf B (2007) Discovery of a potent, selective, and orally active human epidermal growth factor receptor-2 sheddase inhibitor for the treatment of cancer. J Med Chem 50:603–606

    CAS  PubMed  Google Scholar 

  • Zhang C, Lovering F, Behnke M, Zask A, Sandanayaka V, Sun L, Zhu Y, Xu W, Zhang Y, Levin JI (2009) Synthesis and activity of quinolinylmethyl P1’ α-sulfone piperidine hydroxamate inhibitors of TACE. Bioorg Med Chem Lett 19:3445–3448

    CAS  PubMed  Google Scholar 

  • Zask A, Gu Y, Albright JD, Du X, Hogan M, Levin JI, Chen JM, Killar LM, Sung A, DiJoseph JF, Sharr MA, Roth CE, Skala S, Jin G, Cowling R, Mohler KM, Barone D, Black R, March C, Skotnicki JS (2003) Synthesis and SAR of bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors. Bioorg Med Chem Lett 13:1487–1490

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rajeshwar P. Verma .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Basel AG

About this chapter

Cite this chapter

Verma, R.P. (2012). Hydroxamic Acids as Matrix Metalloproteinase Inhibitors. In: Gupta, S. (eds) Matrix Metalloproteinase Inhibitors. Experientia Supplementum, vol 103. Springer, Basel. https://doi.org/10.1007/978-3-0348-0364-9_5

Download citation

Publish with us

Policies and ethics