Design and synthesis of novel metalloproteinase inhibitors

Nakatani, Shingo; Ikura, Masahiro; Yamamoto, Shingo; Nishita, Yoshitaka; Itadani, Satoshi; Habashita, Hiromu; Sugiura, Tsuneyuki; Ogawa, Koji; Ohno, Hiroyuki; Takahashi, Kanji; Nakai, Hisao; Toda, Masaaki

doi:10.1016/j.bmc.2006.03.032

Cited by 23 publications

(13 citation statements)

References 13 publications

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“…A contributing factor to the effectiveness of hydroxamates is the hydrogen bonding that results between the heteroatoms of the ZBG and neighboring amino acid residues that are conserved in all MMP active sites. Several hydroxamate- and carboxylate-based MMPIs show good selectivity among different MMPs (Cherney et al, 2004; Rossello et al, 2005; Nakatani et al, 2006; Whitlock et al, 2007; Subramaniam et al, 2008). Although hydroxamate MMPIs are potent inhibitors, many of them have shown adverse musculoskeletal side effects and poor oral bioavailability (Vihinen et al, 2005; Fingleton, 2008).…”

Section: Modulators Of Mmp Activitymentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigative Tools in the Pathogenesis and Management of Vascular Disease

Benjamin

Khalil

2012

Experientia Supplementum

133

139

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Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade various components of the extracellular matrix (ECM). MMPs could also regulate the activity of several non-ECM bioactive substrates, and consequently affect different cellular functions. Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others. Pro-MMPs are cleaved into active MMPs, which in turn act on various substrates in the ECM and on the cell surface. MMPs play an important role in the regulation of numerous physiological processes including vascular remodeling and angiogenesis. MMPs may also be involved in vascular diseases such as hypertension, atherosclerosis, aortic aneurysm, and varicose veins. MMPs also play a role in the hemodynamic and vascular changes associated with pregnancy and preeclampsia. The role of MMPs is commonly assessed by measuring their gene expression, protein amount, and proteolyic activity using gel zymography. Because there are no specific activators of MMPs, MMP inhibitors are often used to investigate the role of MMPs in different physiologic processes and in the pathogenesis of specific diseases. MMP inhibitors include endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline and marimastat. MMP inhibitors have been evaluated as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. Although several MMP inhibitors have been synthesized and tested both experimentally and clinically, only on MMP inhibitor, i.e. doxycycline, is currently approved by the Food and Drug Administration. This is mainly due to the undesirable side effects of MMP inhibitors especially on the musculoskeletal system. While most experimental and clinical trials of MMP inhibitors have not demonstrated significant benefits, some trials still showed promising results. With the advent of new genetic and pharmacological tools, disease-specific MMP inhibitors with fewer undesirable effects are being developed and could be useful in the management of vascular disease.

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Section: Modulators Of Mmp Activitymentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigative Tools in the Pathogenesis and Management of Vascular Disease

Benjamin

Khalil

2012

Experientia Supplementum

133

139

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“…Our experiments showed that with borane methyl sulfide (BMS)-NaBH 4 , the chemoselective reduction of ester 3 could be achieved and gave the diol 4 in good yield, according to the literature precedents. [27][28][29][30][31] The reason for the chemoselectivity was discussed by Moriwake et al 54 The best ratio for BMS: NaBH 4 :ester 3 was 1:0.1:1. Excess BMS could lead to over-reduction and thus lower yield was obtained.…”

Section: Resultsmentioning

confidence: 97%

Chiral Pool Synthesis of N-Cbz-cis-(3R,4R)-3-methylamino-4-methylpiperidine from L-Malic acid

Hao¹,

Liu²,

Zhang³

et al. 2013

Bulletin of the Korean Chemical Society

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“…Further modifications of N-benzoyl -aminobutanoic hydroxamic acid (I577), carried out by Nakatani et al [127] led to new inhibitors of MMP-2 and MMP-9 with single-double digit nanomolar activities ( Table 19). Analogues containing benzofuran-2-yl in the paraposition of the N-benzoyl residue are the most effective inhibitors of both gelatinases.…”

Section: -Aminobutanoic Hydroxamatesmentioning

confidence: 98%

MMP-2 Selectivity in Hydroxamate-Type Inhibitors

Serra

Bruczko²,

Zapico³

et al. 2012

CMC

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Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents.

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Design and synthesis of novel metalloproteinase inhibitors

Cited by 23 publications

References 13 publications

Matrix Metalloproteinase Inhibitors as Investigative Tools in the Pathogenesis and Management of Vascular Disease

Matrix Metalloproteinase Inhibitors as Investigative Tools in the Pathogenesis and Management of Vascular Disease

Chiral Pool Synthesis of N-Cbz-cis-(3R,4R)-3-methylamino-4-methylpiperidine from L-Malic acid

MMP-2 Selectivity in Hydroxamate-Type Inhibitors

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