Identification of potent and selective MMP-13 inhibitors

doi:10.1016/j.bmcl.2005.06.019

Bioorganic & Medicinal Chemistry Letters

Volume 15, Issue 18, 15 September 2005, Pages 4105-4109

https://doi.org/10.1016/j.bmcl.2005.06.019 Get rights and content

Abstract

A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 μM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.

Graphical abstract

A potent, selective series of MMP-13 inhibitors has been derived from a weak inhibitor that did not bear a zinc chelator.

Section snippets

Acknowledgments

The authors thank Dr. Nelson Huang, Dr. Yin Ge, and Dr. Walter Massefski for LC–MS, HRMS, and NMR measurements, Dr. Kristina Cunningham and Dr. Priya Chockalingham for MMP assay data, Dr. Xuifen Yang for cartilage explant data, and Dr. Qin Wang for PK data. The authors would also like to thank Dr. Anita Chan and Mr. Jean Schmid for preparing large scale quantities of compound 2.

References and notes (25)

V. Knauper et al.
J. Biol. Chem.
(1996)
L.A. Reiter et al.
Bioorg. Med. Chem. Lett.
(2004)
D.P. Becker et al.
Bioorg. Med. Chem. Lett.
(2001)
J.N. Freskos et al.
Bioorg. Med. Chem. Lett.
(1999)
K. Holmbeck et al.
Cell
(1999)
J.S. Skotnicki et al.
Curr. Opin. Drug Disc. Dev.
(2003)
G.R. Tardif et al.
J. Mod. Rheumatol.
(2004)
P.G. Mitchell et al.
J. Clin. Invest.
(1996)
R.C. Billinghurst et al.
Arthritis Rheum.
(2000)
A.H. Drummond et al.
Ann. NY Acad. Sci.
(1999)

J.W. Hutchinson et al.

J. Bone Joint Surg. (Br.)

(1998)

Z. Zhou et al.

Proc. Natl. Acad. Sci. U.S.A.

(2000)

Cited by (61)

Isolation, synthesis and medicinal chemistry of biphenyl analogs – A review
2023, Results in Chemistry
The scaffold-based drug design has been widely used in new drug discovery. Biphenyl and its analog scaffold are found in many drugs and naturally occurring compounds. To date an array of synthetic methodologies have been introduced to access biphenyl analogs with good yield. Biphenyl scaffolds have shown wide range of biological activities such as anti-inflammatory, antihypertensive, treatment of CNS disorders, anti-cancer, anti-HIV, etc. Also, the importance of biphenyl atropisomers is discussed. This review aims to highlight the evidence of biphenyl motif as a privileged scaffold in various natural products and anticancer agents.
Therapeutic effects of kefir peptides on adjuvant-induced arthritis in rats through anti-inflammation and downregulation of matrix metalloproteinases
2023, Life Sciences
Rheumatoid arthritis (RA) is a chronic autoimmune disease. Its pathological features are synovial inflammation, bone erosion, and joint structural damages. Our previous studies have shown that kefir peptides (KPs) can reduce cardiovascular disease, osteoporosis and renal inflammation. In this study, we further evaluate the efficacy of KPs on adjuvant-induced arthritis (AIA) in a rat model.
After the 14th day of adjuvant induction, rats were subsequently orally administered KPs (83 or 166 mg/day/kg) or tofacitinib (6.2 mg/day/kg) for 14 days. On the 28th day, the rats were anesthetized with isoflurane for ultrasonic, in vivo imaging system (IVIS), and radiographic imaging and then sacrificed for ankle tissues collection and analysis. In vitro, IL-1β-treated human synovial cells (SW982) were subjected to anti-arthritis mechanism study in the presence of KPs.
The results of ultrasonography, radiograph, histology, the expression of matrix metalloproteinases (MMPs), inflammatory cytokines and RANKL/OPG ratio demonstrated decreasing severity of synovitis and bone erosion in the ankle joints after KPs treatment. Activation of the NF-κB and MAPK pathways was significantly reduced in KPs treated AIA group. Furthermore, KPs attenuated IL-1β-induced inflammatory cytokine production and the expression of MMPs in a human synovial cell line SW982. These results demonstrated that KPs alleviated adjuvant-induced arthritis in rats by inhibiting IL-1β-related inflammation and MMPs production.
We concluded that KPs can exhibit anti-inflammatory effects by reducing the levels of macrophage-related inflammatory cytokines and MMPs, thus alleviating bone erosion in the ankle joint and constituting a potential therapeutic strategy for rheumatoid arthritis.
Arylsulfonamides and selectivity of matrix metalloproteinase-2: An overview
2017, European Journal of Medicinal Chemistry
Citation Excerpt :
Substitution of the sulfonamide amine function with the methyl, 3-picolyl or the methyloxyethyl group yielded highly effective and selective MMP-2 inhibitors over other MMPs (Site IV, Fig. 36). Wu et al. [105] reported a series of benzofuran carboxamide biphenyl sulfonamide carboxylic acids and evaluated these against MMP-2, -13 and -14. Most of these derivatives were highly potent (activity in lower nanomolar concentration) and selective towards MMP-13 compared to MMP-2 and -14.
Uncontrolled regulation of specific metalloenzymes plays important roles in several diseases like tumor metastasis and inflammation. Therefore, selective metalloenzyme inhibition may be a potential target for drug design and development. Matrix metalloproteinase inhibitors (MMPIs) opened up a new horizon as the possible treatment of arthritis, cancer, and emphysema. However, due to adverse effects and poor pharmacokinetics, first generation MMPIs failed in clinical trials. Therefore, development of potential and selective MMPIs is still in demand. Moreover, the flexibility of the enzyme S1′ pocket is variable in length and shape making the designing approach more challenging. In this article, arylsulfonamides have been highlighted as potential and selective MMP-2 inhibitors through structure-activity relationships study. It may be postulated that sulfonamide moiety may provide better direction to the associated aryl group to accommodate the deep hydrophobic S1′ pocket. Tetrahedral geometry of the sulfonyl function may be favorable than planar carboxyl function regarding the interaction between the aryl group and S1′ pocket. Hydroxamates may impart higher inhibition than corresponding carboxylates due to additional hydrogen bonding. Moreover, MMP-2 selectivity is not only dependent on zinc binders but also on the aryl functions directed towards S1 and S2′ pockets. Therefore, this review may help in designing potential and selective MMP-2 inhibitors.
Trivalent metal ions based on inorganic compounds with in vitro inhibitory activity of matrix metalloproteinase 13
2016, Enzyme and Microbial Technology
Citation Excerpt :
Until now, MMP-13 inhibitors have been identified mainly viahigh-throughput screening (HTS) in the synthetic compound library. Hydroxamic acid is a typical inhibitor for MMP-13 and the reaction mechanism for this activity has been suggested to be due to a functional group that is able to coordinate the central zinc(II) ion to two oxygen atoms via a bidentate ligand interaction [36–39]. In our previous work, Al3+ has been shown to exhibit strong inhibitory effects on both MMP-2 and MMP-9 using a HT1080 cell line [31].
Collagenase-3 (MMP-13) inhibitors have attracted considerable attention in recent years and have been developed as a therapeutic target for a variety of diseases, including cancer. Matrix metalloproteinases (MMPs) can be inhibited by a multitude of compounds, including hydroxamic acids. Studies have shown that materials and compounds containing trivalent metal ions, particularly potassium hexacyanoferrate (III) (K₃[Fe(CN)₆]), exhibit cdMMP-13 inhibitory potential with a half maximal inhibitory concentration (IC₅₀) of 1.3 μM. The target protein was obtained by refolding the recombinant histidine-tagged cdMMP-13 using size exclusion chromatography (SEC). The secondary structures of the refolded cdMMP-13 with or without metal ions were further analyzed via circular dichroism and the results indicate that upon binding with metal ions, an altered structure with increased domain stability was obtained. Furthermore, isothermal titration calorimetry (ITC) experiments demonstrated that K₃[Fe(CN)₆]is able to bind to MMP-13 and endothelial cell tube formation tests provide further evidence for this interaction to exhibit anti-angiogenesis potential. To the best of our knowledge, no previous report of an inorganic compound featuring a MMP-13 inhibitory activity has ever been reported in the literature. Our results demonstrate that K₃[Fe(CN)₆] is useful as a new effective and specific inhibitor for cdMMP-13 which may be of great potential for future drug screening applications.
Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors
2016, Bioorganic and Medicinal Chemistry
Citation Excerpt :
MMPs such as MMP-2, MMP-3, MMP-8, MMP-9, MMP-12, MMP-13, and MMP-14 have large S1′ pockets and can accommodate more diverse large P1′ groups. Thus, targeting the large S1′ loop region assists in identifying MMP-13-specific inhibitors.19–28,48–52 As mentioned above, we described the discovery of potent MMP-13 inhibitors which form β-sheet type hydrogen bond interactions with both Thr245 and Thr247 of the S1′ site.
Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1′ binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC₅₀ = 0.071 nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.
Modeling, predicting and virtual screening of selective inhibitors of MMP-3 and MMP-9 over MMP-1 using random forest classification
2015, Chemometrics and Intelligent Laboratory Systems
Citation Excerpt :
The original data sets of compounds with known half maximal inhibitory concentration (IC50) used in this study encompassed 111 MMP-3 sparing MMP-1 inhibitors, 184 MMP-9 sparing MMP-1 inhibitors, 184 both MMP-3 and MMP-9 non-inhibitors, 310 MMP-1 broad spectrum inhibitors and 539 MMP non-inhibitors, covering a broad range. There were a large quantity of MMP inhibitors manually extracted from several published papers [7,9,19–27,29,42,50–89]. These molecules are distributed in various structural groups such as aminopyrrolidine-based hydroxamate inhibitors, biphenylsulfonamide derivatives, cyclic phosphon- and phosphinamide-based hydroxamic acids, cyclopentane carboxylic acids, biaryl ether retrohydroxamates, biphenylsulfonylaminobutylhydroxamic acids, sulfone carboxylic acids and so on [19,20,23,24,67,76,88].
Over-expression of matrix metalloproteinases (MMPs) has been linked to a variety of serious pathological disorders. Methods of predicting and screening vigorous and selective MMP inhibitors are urgently needed for facilitating the design and development of novel therapeutic agents. Two machine learning methods, support vector machine (SVM) and random forest (RF), were explored to develop prediction models for diversely structural selective inhibitors of MMP-3 over MMP-1 and MMP-9 versus MMP-1 in this work, individually. The developed models were validated by testing sets and external independent validation sets, showing satisfactory performance. The physicochemical properties most extensively concerned with MMP-3 and MMP-9 selective inhibition were extracted from a set of 189 descriptors by feature selection methods, which are capable of competently describing most of the molecular features of these inhibitors. The molecular descriptors most relevant to MMP-1 inhibitors were also derived from these 189 features. All those properties provide an excellent analytical perspective to explain the similarities and differences to MMP-1, MMP-3 and MMP-9 inhibitors in structure or function. Finally, the virtual screening of MMP-1, MMP-3 and MMP-9 inhibitors against the SCdatabase were separately performed based on the RF model which is slightly better than the SVM method, resulting in 110 potential hit candidates for MMP-3 over both MMP-1 and MMP-9, 23 hits for MMP-9 versus both MMP-1 and MMP-3, and 80 hits for MMP-3 and MMP-9.

View all citing articles on Scopus

View full text

Identification of potent and selective MMP-13 inhibitors

Abstract

Graphical abstract

Section snippets

Acknowledgments

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Cell

Curr. Opin. Drug Disc. Dev.

J. Mod. Rheumatol.

J. Clin. Invest.

Arthritis Rheum.

Ann. NY Acad. Sci.

J. Bone Joint Surg. (Br.)

Proc. Natl. Acad. Sci. U.S.A.