Metalloprotease inhibitors are cellular inhibitors of the Matrix metalloproteinases (MMPs). MMPs belong to a family of zinc-dependent neutral endopeptidases. These enzymes have the ability to break down

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

. The expression of MMPs is increased in various pathological conditions like inflammatory conditions, metabolic bone disease, to cancer invasion, metastasis and

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

. Examples of diseases are periodontitis, hepatitis, glomerulonephritis, atherosclerosis,

emphysema Emphysema, or pulmonary emphysema, is a lower respiratory tract disease, characterised by air-filled spaces ( pneumatoses) in the lungs, that can vary in size and may be very large. The spaces are caused by the breakdown of the walls of the alve ...

, asthma, autoimmune disorders of skin and dermal photoaging, rheumatoid arthritis, osteoarthritis,

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

, chronic ulcerations, uterine involution,

corneal epithelial defects The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical powe ...

, bone resorption and tumor progression and metastasis. Due to the role of MMPs in pathological conditions, inhibitors of MMPs may have therapeutic potential. Several other proteins have similar inhibitory effects, however none as effective (netrins, procollagen C-terminal proteinase enhancer (PCPE), reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and tissue factor pathway inhibitor (TFPI-2)). They might have other biological activities which have yet been fully characterised. MMP inhibitors can broadly be subdivided into non-synthetic (e.g.

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

) or

synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

. Several potent MMP inhibitors have been identified, including hydroxymates, thiols, carbamoylphosphonates, hydroxyureas,

hydrazine Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...

s, β-lactams, squaric acids and nitrogenous ligands. There are three classes of commonly used inhibitors for metalloproteinases. * ''In vitro'', EDTA,

1,10-phenanthroline 1,10-Phenanthroline (phen) is a heterocyclic organic compound. It is a white solid that is soluble in organic solvents. The 1,10 refer to the location of the nitrogen atoms that replace CH's in the hydrocarbon called phenanthrene. Abbreviated ...

and other chelating compounds lower the concentration of metal to the point where the metal is removed from the enzyme

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...

. * Classical lock and key inhibitors such as

phosphoramidon Phosphoramidon is a chemical compound derived from cultures of '' Streptomyces tanashiensis''. It is an inhibitor of the enzyme thermolysin, of the membrane metallo-endopeptidase,bestatin bind tightly by approximating the transition state of the hydrolysis of the peptide, preventing it from acting on other substrates. * Protein inhibitors such as α2- macroglobulin are known to work with metalloproteinases.

History

The first generation of MMP inhibitors were based on the structure of the

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

molecule. This group of inhibitors contain a hydroxamate (-CONHOH) group that binds the zinc atom in the active site of the MMP enzyme. The first MMP inhibitors that were tested in patients were

Ilomastat Ilomastat (INN), (codenamed GM6001, proprietary name Galardin®) is a broad-spectrum matrix metalloproteinase inhibitor. This chemotherapy agent is considered to have application in skincare products for its antiaging properties. Ilomastat is a ...

and

Batimastat Batimastat (mnemonic: ''batty''-mustard) (INN/USAN, codenamed BB-94) is a drug that was invented by Laurie Hines of British Biotech (now Vernalis). It is an antimetastatic drug that belongs to the family of drugs called angiogenesis inhibitors. ...

, hydroxamate-based MMP inhibitors. However, neither compound showed good oral bioavailability.
Thus far,

Periostat Doxycycline is a broad-spectrum tetracycline class antibiotic used in the treatment of infections caused by bacteria and certain parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, and ...

(active ingredient is doxycycline hyclate) is the only MMP inhibitor that has been approved by the U.S. Food and Drug Administration (FDA). It is used for the treatment of periodontitis. Other MMP inhibitors have exhibited serious side effects during preclinical trials. These side effects are caused by insufficient

selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...

. Most MMP inhibitors are unable to target specific MMPs connected to specific pathological conditions. Instead, they inhibit multiple MMPs, some of which have protective functions or are not related to pathology.
MMPs have been regarded as promising targets for cancer therapy. Preclinical studies investigating the efficacy of MMP suppression in tumor models were encouraging. Following these results, clinical studies were conducted but turned out to be disappointing. Recent studies have shown that MMPs may even have paradoxical roles in tumor progression. MMPs seem to have tumor-promoting effects as well as tumor suppressive effects dependent on different contexts.

Mechanism of action

EndogenousAndPharmacologicalInhibitorsOfMMPReduziert

Most MMP inhibitors are

chelating agent Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...

s. The inhibitor binds to the zinc at the active center of the enzyme, thereby blocking its activity. Other inhibitor mechanisms are possible.
α2-Macroglobulin (α2M) is a protease inhibitor which inhibits activated MMPs. α2M and MMP form a complex which is able to inactivate the MMP.
MMPs are associated with the cell surface or bound to the extracellular matrix which prevents them from diffusing away and keeps the MMP under control of the cell. One

mechanism Mechanism may refer to: *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission *Mechanism (biology), explaining how a feature is created *Mechanism (philosophy), a theory that a ...

to inhibit MMP activity is by dislodging the enzymes from their receptors. Gold salts bind to a heavy metal site distinct form the zinc-containing active center, which inhibits their activity. MMP activity can be decreased by binding to the cleavage site on the

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...

e.g. catechin.
Two

molecular A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...

features of most MMP inhibitors are responsible for the

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Partn ...

. One is a chelating

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

that interacts with the zinc ion and the other is a hydrophobic extension from the catalytic site that project into S1’ pocket (P1’ group) of the metalloproteinase. The structural difference MMPs’ is mainly in the S1’ side and by modifying the P1’ group, inhibitor selectivity can be developed.

Drug development

Various potential MMP inhibitors will be explained in the following sections, including information on their development, structure-activity relationship and pharmacokinetics.

Pioneering hydroxamate structures

The first generation of MMP inhibitors were based on the structure of the collagen molecule. In the design of these inhibitors, the basic protein backbone of collagen is maintained but the

amide bond In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is p ...

is replaced with a zinc-binding group. This group of inhibitors contain a hydroxamate (-CONHOH) group that binds the zinc atom in the active site of the MMP enzyme, therefore this group is called "hydroxamate-based MMP inhibitors“. An example can be seen in

Marimastat Marimastat was a proposed antineoplastic drug developed by British Biotech. It acted as a broad-spectrum matrix metalloproteinase inhibitor A matrix metalloproteinase inhibitor (MMPI) inhibits matrix metalloproteinases. As they inhibit cell mi ...

, a first generation inhibitor, which has a similar backbone and sidechain format to collagen. Collagen and marimastat

and

batimastat Batimastat (mnemonic: ''batty''-mustard) (INN/USAN, codenamed BB-94) is a drug that was invented by Laurie Hines of British Biotech (now Vernalis). It is an antimetastatic drug that belongs to the family of drugs called angiogenesis inhibitors. ...

were the first two MMP inhibitors to be tested in patients. These are both hydroxamate-based MMP inhibitors and have similar overall structures. Marimastat, batimastat and ilomastat

The hydroxamate-based MMP inhibitors display an excellent anticancer activity in tumor cells but the clinical performances of these compounds were disappointing. A factor contributing to this disappointment was that they are broad-spectrum inhibitors of many MMP sub-types that can in many cases also inhibit members of the ADAMs protease family. When they were tested in patients they induced dose-limiting muscular and

skeletal A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...

pain in a number of the patients. Only when the structures of the MMP inhibitors could be adjusted to impart selectivity and abolish toxicity, would they achieve clinical impact in cancer chemotherapy.

New generation hydroxamate-based inhibitors

The pioneering hydroxamate-based inhibitors were followed by a set of 'new generation' molecules with features including a

substituted A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...

aryl, a

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...

and a hydroxamate zinc-binding group. Hydroxamate-based MMP inhibitors

In MMI-270 there is also an amino acid sidechain-type substituent on the carbon that is α to the hydroxamate, along with a sidechain on the sulfonamide (which was later shown to be unnecessary). The N-arylsulfonyl-α-aminoacid hydroxamate of MMI-270 mimics the marimastat succinate motif.

Cipemastat Cipemastat (rINN, also known as Ro 32-3555 and by the tentative trade name Trocade) is a selective inhibitor of matrix metalloproteinase-1 that has been investigated as an anti- arthritis agent. It is being developed by Roche F. Hoffmann-L ...

, which was developed as an

MMP-1 Interstitial collagenase, also known as fibroblast collagenase, and matrix metalloproteinase-1 (MMP-1) is an enzyme that in humans is encoded by the ''MMP1'' gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. ...

, -3 and -9 collagenase inhibitor for the treatment of

rheumatoid Rheumatism or rheumatic disorders are conditions causing chronic, often intermittent pain affecting the joints or connective tissue. Rheumatism does not designate any specific disorder, but covers at least 200 different conditions, including art ...

- and osteo-arthritis, also has the marimastat succinate motif. Its clinical trial was terminated prematurely.
MMI-166 has an N-arylsulfonyl-α-aminocarboxylate zinc-binding group, different from the hydroxamate-zinc binding group seen in MMI-270 and Cipemastat. It also has a triaryl substitution that the other structures didn‘t have. ABT-770 and

Prinomastat Prinomastat (code name AG-3340) is a matrix metalloproteinase (MMP) inhibitor with specific selectivity for MMPs 2, 3, 9, 13, and 14. Investigations have been carried out to determine whether the inhibition of these MMPs is able to block tumour ...

also have an aryl substitution. In ABT-770 the two phenyl rings are directly connected but in Prinomastat the two

phenyl ring In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...

s are connected by an oxygen atom, forming a

diphenylether Diphenyl ether is the organic compound with the formula ( C6 H5)2 O. It is a colorless solid. This, the simplest diaryl ether, has a variety of niche applications. Synthesis and reactions Diphenyl ether and many of its properties were first rep ...

. These three permutations direct the

SAR SAR or Sar may refer to: Places * Sar (river), Galicia, Spain * Sar, Bahrain, a residential district * Sar, Iran (disambiguation), several places in Iran * Sar, Tibet, Tibet Autonomous Region of China * Šar Mountains, in southeastern Europe ...

away from MMP-1 and toward the „deep pocket“ MMPs such as the gelatinases. ABT-770 shows anticancer activity in animal models, but it is easily metabolised to an amine

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

that causes

phospholipidosis Phospholipidosis is a lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues. Certain cases may be triggered by medications. The traditional method to evaluate drug-induced phospholipidosis (DIPL) is visua ...

. MMI-166 has shown anticancer activity in numerous animal models, but there is no data available of its clinical performance. Prinomastat on the other hand, is one of the best studied MMP inhibitors. It showed excellent preclinical animal anticancer

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a pragmatic clinical trial#Efficacy versu ...

, but a recurring limitation to these hydroxamates (Prinomastat in particular) is drug metabolism including loss of the hydroxamate zinc-binding group. New generation hydroxamate-based MMP inhibitors

New generation hydroxamate-based MMP inhibitors

These inhibitors were followed by the next group of hydroxamate-based inhibitors, which focus on the suppression of metabolism, minimization of MMP-1 inhibitory activity and the control of subtype selectivity, by structure-based design. The tetrahydropyran in RS-130830 introduces a

steric Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...

block that suppresses metabolism, which would fix the problem that the previous generation of inhibitors showed. The outcome of its clinical evaluation has not yet been disclosed. 239796-97-5 has improved

ADME ADME is an abbreviation in pharmacokinetics and pharmacology for " absorption, distribution, metabolism, and excretion", and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug le ...

and MMP-1 selectivity properties and has shown excellent oral efficacy in an animal model of osteoarthritis. Although, the therapeutic objectives for these inhibitors is not cancer, like it has been for most of the MMP inhibitors.

New generation thiol-based inhibitors

Rebimastat is a broad spectrum MMP inhibitor with a thiol zinc-binding group. It has oral bioavailability and is a collagen non-peptide mimetic. Rebimastat has some selectivity as it doesn't inhibit all the MMPs operations. The metalloproteinases that release TNF-alpha, TNF-II, L-selectin, IL-1-RII and IL-6 are for example not inhibited by Rebimastat.
In phase I of

clinical trials Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

, there was no sign of dose-dependent joint toxicity and a disease stabilization. Arthralgia was noted in phase II early breast cancer trials, which was connected to MMP inhibitor toxicity. Rebimastat was used in a Paclitaxel/ Carboplatin treatment in phase III. The results of the trial was a higher incidence of

adverse reaction An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...

s, without survival benefit.

Clinical trials for

Tanomastat Tanomastat is a matrix metalloproteinase inhibitor (MMPI). Excision of malignant tumors comprises first line treatment for cancer of solid tissues. This procedure not infrequently misses small fragments of the tumor that may have broken off befor ...

, an alfa-((phenylthio)methyl)carboxylate, showed similar results. It showed good disease stability and tolerance in Phase I solid tumor trials and good tolerance in advanced cancer in combination with Etoposide. However, its efficacy was not proven to be adequate. Tanomastat showed significant hepatotoxicity in a cancer therapy combined with Cisplatin and Etoposide, although in a treatment with Doxorubicin it showed good tolerance and lowered toxicity with

5-fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...

and Leucovorin.
Many compounds in the thiol zinc-binding groups have good water solubility and are air stable in

plasma Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral), a green translucent silica mineral * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood pla ...

and these groups will be continued in MMP inhibitor designing.

Pyrimidine-based inhibitors

Ro 28-2653 is highly selective for

MMP-2 72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the ''MMP2'' gene. The ''MMP2'' gene is located on chromosome 16 at position 12.2. Function Proteins of the ...

, MMP-9 and membrane type 1 ( MT-1)-MMP. It is an antitumor and antiangiogenic agent with oral bioavailability. Inhibition of TACE and MMP-1 are linked to the musculoskeletal side effects seen in hydroxamate metalloproteinase inhibitors, but this compound spares the enzymes. It has been shown to diminish tumor growth in

nasal Nasal is an adjective referring to the nose, part of human or animal anatomy. It may also be shorthand for the following uses in combination: * With reference to the human nose: ** Nasal administration, a method of pharmaceutical drug delivery ** ...

cancer in rats as well as prostate cancer

cell culture Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...

s. The compound only has moderate effect on mice's adipose tissue and no alteration on joints. Based on this, it is concluded that class of inhibitors is less likely to

trigger Trigger may refer to: Notable animals and people ;Mononym * Trigger (horse), owned by cowboy star Roy Rogers ;Nickname * Trigger Alpert (1916–2013), American jazz bassist * "Trigger Mike" Coppola (1900–1966), American gangster ;Surname * Bru ...

neuromuscular adverse effects. On the active site of the structure is a

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...

trione chelation and the phenyl and piperidynil section occupy the S1’ and S2’ binding pockets of MMP-8. Compound 556052-30-3 is similar to Ro 28-2653 but incorporates a 4-((2-methylquinolin-4-yl)methoxy)phenyl sidechain that is TACE selective.
5-(spiropyrrolidin-5-yl)pyrimidinetrione is a compound named 848773-43-3 that is a potent MMP-2, MMP-9 and MMP-13 inhibitor that spares MMP-1 and TACE.
By substituting 1,3,4-oxadiazol-2-yl heteroaryl at C-4’ of the diphenylether segment to accomplish

MMP-13 Collagenase 3 is an enzyme that in humans is encoded by the ''MMP13'' gene. It is a member of the matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form. MMP-13 has an predicted molecular weight around 54 kDa. ...

selectivity over MT-1 MMP, made the compound 420121-84-2. The compound has IC₅₀ (half maximal inhibitory concentration) of 1 nM for MMP-13.
I125-radioable pyrimidinetriones that have similar structure have been made to be used in MMP-9 elevated atherosclerosis and elevated MMP-2 and MMP-9 cancers.
This class of MMP inhibitors is easy to synthesize and are potent enough for clinical valuation. CAS Reg

Compound 544678-85 is the latest pyrimidine based inhibitor, the compound is a pyrimidine-4,6-dicarboxamide that is very potent and MMP-13 selective. The compound has a specificity loop that within the S1’ pocket and its 3-methyl-4-fluoro group is proximal enough to the zinc to change the water entity. These compounds have good oral bioavailability and properties that promote them to be a good candidate for a subtype inhibitor of MMP-13 based diseases and future development.
Pyrimidine

dicarboxamide Dicarboximide (or dicarboxamide) fungicides are a family of agricultural fungicides that include vinclozolin, iprodione, and procymidone. Dicarboximides are believed to inhibit triglyceride biosynthesis in sclerotia-forming fungi, including ''Botry ...

s are highly selective MMP-13 inhibitors. In the S1’ pocket of MMP-13 is an S1’ side pocket that is unique to the matrix metalloproteiase. Pyrimidine dicarboxamides bind to this side pocket, which increases the selectivity. The role of MMP-13 is cleaving fibrillar collagen at neutral pH and higher mRNA levels of MMP-13 is detected in breast

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...

and osteoarthritis joints. The pyrimidine dicarboxamide inhibitor example in the image does not interact with the catalytic zinc ion but rather binds to the S1’ side pocket. One pyridyl arm is situated to the entrance of the S1’ pocket while the other pyridyl arm goes through the S1’ pocket into the side pocket.

Hydroxypyrone-based inhibitors

Potent and selective MMP-3 inhibitors have been developed by using a hydroxypyrone as the zinc binding group. By attaching an aryl backbone to the 2-position of the

pyrone Pyrones or pyranones are a class of heterocyclic chemical compounds. They contain an unsaturated six-membered ring containing one oxygen atom and a ketone functional group. There are two isomers denoted as 2-pyrone and 4-pyrone. The 2-pyrone (or ...

ring, more selectivity was gained. On the hydroxypyrone ring, three positions are available to attach backbones, position 2-, 5- and 6-.
Hydroxypyrone-based MMP inhibitors are structurally corresponding to the pyrimidinetriones. A recent inhibitor is the compound 3-hydroxypyran-4-one nominated 868368-30-3. It is MMP-3 selective and its 0,0- bidentate chelation of zinc is the structural part proposed to be responsible for the MMP

recognition Recognition may refer to: *Award, something given in recognition of an achievement Machine learning *Pattern recognition, a branch of machine learning which encompasses the meanings below Biometric * Recognition of human individuals, or biomet ...

Phosphorus-based inhibitors

Investigation on MMP inhibitors with phosphorus based zinc binding groups focused on α-biphenylsulfonylamino phosphonates. These inhibitors bind through two phosphonate oxygen atoms. Phosphonate inhibitors have been developed that exhibit selectivity for MMP-8 over other MMPs. Selective MMP-8 inhibitors could be useful in the treatment of acute liver disease and

Phosphinic MMP inhibitors have been reported to target MMP-11 and MMP-13. MMP-13 plays a role in

cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...

degradation in osteoarthritis. These phosphinate MMP inhibitors contain phenyl segments that are thought to be responsible for the selectivity to MMP-13. The phosphinic group of those inhibitors (R¹R² (O)OH) binds as a zinc ligand. R¹ and R² substituents affect the inhibition potency.
Phosphinate inhibitors have been developed that showed high selectivity for MMP-11.

Derivatives The derivative of a function is the rate of change of the function's output relative to its input value. Derivative may also refer to: In mathematics and economics * Brzozowski derivative in the theory of formal languages * Formal derivative, an ...

based on phenyl rings showed the best selectivity. MMP-11 could be a useful target for tumorgenesis in breast cancer. Binding mode of carbamoylphosphonate to the zinc active site of MMP

Binding mode of carbamoylphosphonate to the zinc active site of MMP

Phosphorus-based inhibitors with

carbamoyl Carbamic acid, which might also be called aminoformic acid or aminocarboxylic acid, is the chemical compound with the formula . It can be obtained by the reaction of ammonia and carbon dioxide at very low temperatures, which also yields an equ ...

phosphonate zinc binding groups do not bind through two oxygen of the phosphonate. Carbamoyl phosphonate zinc binding groups binds Zn²⁺ through the oxygen of the phosphonate and the oxygen of the alpha carbonyl to the phosphonate. This binding forms a 5-members chelate ring that looks similar to the binding of hydroxamic acid.
The

of the carbamoyl phosphonate provide a

hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

donor for protein interactions and the amide group has an electron donating ability that provides strong Zn²⁺ chelation. The carbamoyl phosphonate zinc binding groups have a net negative charge that hinders cell penetration of these inhibitors and restricts them to the extracellular space. This cell penetration prevention contributes to the low toxicity of these inhibitors. Inhibitors with a carbamoyl phosphonate zinc-binding group are selective for

. MMP-2 could be a useful

target Target may refer to: Physical items * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artillery, fi ...

for tumor invasion and

. A carbamoyl phosphonate inhibitor has been developed that affects MMP-2 and MMP-9 sparing other MMPs. This compound showed inhibitory activity on cell invasion and tumor

colonization Colonization, or colonisation, constitutes large-scale population movements wherein migrants maintain strong links with their, or their ancestors', former country – by such links, gain advantage over other inhabitants of the territory. When ...

. In in vivo studies, this inhibitor showed efficacy with oral dosing and administration into the

abdominal cavity The abdominal cavity is a large body cavity in humans and many other animals that contains many organs. It is a part of the abdominopelvic cavity. It is located below the thoracic cavity, and above the pelvic cavity. Its dome-shaped roof is the th ...

(intraperitoneal). It shows slow

absorption Absorption may refer to: Chemistry and biology * Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which ...

, rapid elimination and low oral bioavailability. Prolonged absorption contributes to sustained efficacy. Inhibitors with carbamoyl phosphonate zinc binding groups are water-soluble at

physiological Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...

pH.

Tetracycline-based inhibitors

Basic structure of tetracycline chelating a metal

Tetracyclines are antibiotics that also exhibit MMP inhibitory activity. They chelate Zn²⁺ ion, thereby inhibiting MMP activity. It is believed that tetracyclines also effect MMP expression and proteolytic activity. Doxycycline structure

Doxycycline Doxycycline is a broad-spectrum tetracycline class antibiotic used in the treatment of infections caused by bacteria and certain parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, an ...

is a semi-synthetic tetracycline that has been studied for dental and medical applications. Its effects on diseases like periodontitis and cancer has been investigated. Doxycycline is nearly completely absorbed with a bioavailability about 95% in average and a 20% reduction with co-administration of food. Its volume of distribution is 50–80 L (0,7 L/kg).

Protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...

is 82–93 %. It is

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

in urine and in feces. Doxycycline is available in oral and

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

form. Doxycycline exhibited inhibitory activity on MMP-2 and MMP-9. The expression and activity of MMP-2 and MMP-9 are often elevated in human cancer. The increased expression and activity correlates with advanced tumor stage, increased metastasis and

prognosis Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...

.
Chemically modified tetracyclines (CMT) have been developed to explore their inhibitory potential. Most studies in tetracyclines and CMTs showed that they can inhibit MMP activity. COL-3

One CMT called COL-3 or metastat has been demonstrated to be a potent MMP inhibitor. COL-3 features a tetracycline scaffold that is unsubstituted on positions C4–C9.
Advantages of CMT over conventional tetracyclines are that chronic use does not result in gastrointestinal toxicity and higher plasma levels can be achieved for extended time span reducing administration frequency.
The

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of COL-3 has been studied in rats. COL-3 is absorbed slowly from the gastrointestinal tract. 3% are excreted through the urinary tract while 55–66% is excreted in feces. The

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

is highly lipophilic and able to cross the blood brain barrier at higher doses. COL-3 accumulates in higher concentration in heart tissue and testis. In clinical trials plasma protein binding has been shown to be high (~94,5%). Most COL-3 binds to serum albumin.

Endogenous inhibitors

MMP activity is regulated at various levels for example by

inhibitors like α2-macroglobulin and the tissue inhibitors of metalloproteinases (TIMPs).
α2-macroglobulin regulates a broad spectrum of proteases, while TIMPs are more specific endogenous MMP inhibitors. α2-macroglobulin is an abundant plasma protein that acts in tissue fluids. The plasma

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

consists of four subunits. α2-macroglobulin does not inhibit the activation of MMPs or the MMPs themselves. It entraps proteinases like MMPs and forms a complex with them. The complex is endocytosed and cleared by a low-density lipoprotein-receptor-related protein.
In humans, 4 different TIMPs have been found. They are secreted proteins of low- molecular weight. TIMPs bind non covalently to the active site of MMPs. Changes of TIMP levels are considered to play a role in pathological conditions associated with unbalanced MMP activities. TIMPs consist of 184-194 amino acids. These inhibitors are subdivided into two domains

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

and C-terminal. The N-terminal regions of the four TIMPs share a common structure. They all contain twelve

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

residues that form six disulfide bonds. These bonds are critical for the conformation of the N-terminal and its MMP-inhibitory activities. The C-terminals of the TIMPs differ from each other. The N-terminal subunit is capable of inhibiting MMPs. The TIMP molecule form fits into the active site of an MMP. The TIMP contact the catalytic cleft of the MMP in a similarly as a substrate. TIMPs inhibit all MMPs except TIMP-1 which does not inhibit MT-1-MMP.
There are some differences in the inhibitory preferences of TIMPs. TIMP-1 for example favors to inhibit MMP-9. Other examples are TIMP-2 and TIMP-4 which are more potent MMP-2 inhibitors than MMP-9 inhibitors.
TIMPs could potentially be useful against illnesses like

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...

and cancer. The application of TIMPs as therapeutic instrument through gene therapy or direct protein application is still in early stages of development. It is preferable to inhibit specific MPPs that play a role in pathological conditions. Since TIMPs inhibit multiple MMPs it is desirable to develop engineered TIMPs with altered specificity.

Current status

The primary goal of MMP inhibitor design is selectivity. The targeting of specific MMPs is expected to improve efficacy and prevent side effects like musculoskeletal syndrome (MSS). 3D structures of MMP inhibitors provide a source of insight of the structural relationships for selectivity.

High throughput screening High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling ...

can as well increase the chances of discovering inhibitors with high selectivity.

References

{{reflist, 30em

External links

cambridgemedchemconsulting entry

matrix metalloproteinase inhibitors Matrix most commonly refers to: * ''The Matrix'' (franchise), an American media franchise ** ''The Matrix'', a 1999 science-fiction action film ** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchis ...