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 multiple sclerosis phosphinic mmp inhibitors have been reported to target mmp-11 and mmp-13. mmp-13 plays a role in cartilage 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 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 zn2+ active site of mmp phosphorus-based inhibitors with carbamoyl 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 amide bond of the carbamoyl phosphonate provide a hydrogen bond 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. mmp-2 could be a useful target for tumor invasion and angiogenesis. 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. in in vivo studies, this inhibitor showed efficacy with oral dosing and administration into the abdominal cavity (intraperitoneal). it shows slow absorption, rapid elimination and low oral bioavailability. prolonged absorption contributes to sustained efficacy. inhibitors with carbamoyl phosphonate zinc binding groups are water-soluble at physiological ph. tetracycline-based inhibitors basic structure of a tetracycline chelating a metal (m)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 doxycycline 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 is 82–93 %. it is excreted in urine and in feces. doxycycline is available in oral and intravenous 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. 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. chemically modified tetracycline col-3, metastat 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 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 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 endogenous 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 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 noncovalently 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 and c-terminal. the n-terminal regions of the four timps share a common structure. they all contain twelve cysteine 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 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 can as well increase the chances of discovering inhibitors with high selectivity.