Bisphosphonate Prodrugs Research Articles

Bisphosphonate Prodrugs. Selective Synthesis of (1-Hydroxyethylidene)-1,1-bisphosphonate Partial Esters

Selective methods for the synthesis of (1-hydroxyeth- ylidene)-1,1-bisphosphonate tri-, P,P -di-, P,P-di- and mono esters have been developed. Preparation is started from selected symmet- ric or unsymmetric tetraesters of etidronate using alkalimetal salts or trimethylsilyl iodide as dealkylating agents. Synthesis of H3CC(OH)(P(O)(OH)2)(P(O)(OH)(OHex)) starting from trimethyl ester of etidronate is also described. 1 H, 13 C and 31 P NMR data are reported including 1 JCP, 2 JCP and 2 JPP couplings. The solid state structure is given for (1-(dimethoxyphosphinyl)-1-hydroxyethyl)- 1-phosphonic acid monomethyl ester monopotassium salt (1a).

Bone-specific delivery and sustained release of diclofenac, a non-steroidal anti-inflammatory drug, via bisphosphonic prodrug based on the Osteotropic Drug Delivery System (ODDS)

We have newly synthesized osteotropic diclofenac with bisphosphonic moiety (DIC-BP) based on the concept of Osteotropic Drug Delivery System (ODDS) and investigated its potency of site-specific and controlled delivery of diclofenac to the bone in rats. After intravenous injection into rats, DIC-BP was predominantly distributed in the skeleton. DIC-BP once incorporated in the bone was gradually eliminated ( t 1/2=9.7 days), releasing diclofenac into the bone compartment. As a result, the bone concentration of regenerated diclofenac was apparently constant over 28 days. Furthermore, we evaluated the anti-inflammatory effects of DIC-BP compared with diclofenac (sodium salt) in adjuvant-induced arthritic rats. The mean effective doses (ED 50) were 0.55 mg/kg and 1.3 mg/kg for daily oral administration of diclofenac and weekly intravenous injection of DIC-BP, respectively. Considering the frequency of medication of 17 times for diclofenac and 4 times for DIC-BP in the experimental period, ED 50 was corrected to 9.4 and 5.2 mg/kg (per experimental period) for diclofenac and DIC-BP, respectively. Moreover, DIC-BP exhibited no side effects of gastrointestinal damage, typical of non-steroidal anti-inflammatory drugs. Thus, ODDS of diclofenac shows promise as an approach for highly potent and non-toxic therapy of diclofenac, with less frequent medication.

Bisphosphonate prodrugs: synthesis and in vitro evaluation of alkyl and acyloxymethyl esters of etidronic acid as bioreversible prodrugs of etidronate

The synthesis and preliminary evaluation of novel alkyl and acyloxymethyl esters of etidronic acid as etidronate prodrugs is reported. Tetramethyl ester of etidronic acid was found be isomerized at pH 7.4 and P–C–P bridge was rearranged to P–C–O–P. This unwanted process was prevented via acylation of the bridging carbon’s alcohol group. Acylation showed to be stable if one or more phosphonic OH– groups were substituted. However, when none of the phosphonic OH– groups were substituted, the acylation was chemically hydrolysed and the parent drug was released. This finding was successfully applied in the design of tetrapivaloyloxymethyl ester of acetylated etidronic acid which released etidronic acid via enzymatic (first step) and chemical (second step) hydrolysis in liver homogenate. However, the corresponding tri-substituted pivaloyloxymethyl ester having adequate water-solubility and lipophilicity (log P app 0.6 at pH 7.4), is probably the most potential prodrug candidate reported to enhance the oral bioavailability of etidronate.

Bisphosphonate prodrugs: unusual dimerisation of clodronic acid trimethyl ester to a cyclic bis(bisphosphonate)

Cl2C[P(O)(OMe)2P(O)(OMe)(O− Z+)] selectively reacts with acetyl chloride to provide a new enzymatically stable heterocyclic bis(bisphosphonate); the structure is confirmed by X-ray crystallography.

Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel acyloxyalkyl esters of clodronic acid.

Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of clodronic acid were synthesized, and their properties as possible prodrugs of clodronate were evaluated in vitro. All pivaloyloxymethyl esters were significantly more lipophilic (log P(app) ranged from -2.1 to 7. 4) than clodronate (log P(app) < or = -5.4), which suggests that it may be possible to change the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradation products were further degraded, and clodronic acid was released in quantitative amounts. In human serum, the stability of pivaloyloxymethyl esters was comparable to their stability in phosphate buffer (pH 7.4), which suggests that their degradation in human serum is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of clodronic acid were also synthesized, but they did not release clodronic acid due to the enzymatic and chemical stability of the formed 3-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.

Bisphosphonate prodrugs: a new synthetic strategy to tetraacyloxymethyl esters of methylenebisphosphonates

A concise and simple method to prepare Cl 2C[P(O)(OCH 2O 2CCMe 3) 2] 2 starting from H 2C[P(O)(OMe) 2] 2 with high selectivity and reasonable yield is developed.

Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel clodronic acid dianhydrides as bioreversible prodrugs of clodronate.

P,P'-Diacetyl, P,P'-dibutyroyl, P,P'-dipivaloyl, and P,P'-dibenzoyl (dichloromethylene)bisphosphonic acid dianhydride disodium salts (2a-d) were synthesized and evaluated as novel bioreversible prodrugs of clodronate. The anhydrides were prepared by reacting anhydrous tetrasodium clodronate with a large excess of the corresponding acid anhydride. The dianhydrides 2a-d alone were more lipophilic than the parent clodronate, as determined by drug partitioning between 1-octanol and phosphate buffer at pH 7.4. They also were stable toward chemical hydrolysis in aqueous solutions (pH 7.4 and 2.0). The half-lives for chemical degradation in a buffer solution at 37 degrees C varied from 0.7 to 286 h and from 15 to 790 h at pH 2.0 and 7.4, respectively. The dianhydrides 2a,b,d underwent complete enzymatic hydrolysis to clodronate in 80% serum at 37 degrees C after 1 min, although 2c had a half-life of 3.3 h. The aqueous solubility of clodronate decreased considerably in the presence of Ca2+ ions. This is most probably due to formation of poorly water-soluble chelates, which may also hinder the oral absorption of clodronate. However, Ca2+ ions did not have an effect on the aqueous solubility of clodronic acid dianhydrides, and therefore, these prodrugs may improve oral absorption of the parent drug. In conclusion, these novel dianhydride derivatives may be potentially useful prodrugs of clodronate which, due to their lipophilicity and lack of Ca2+ chelating, increase its bioavailability after oral administration.

Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel partial amides of clodronic acid

Novel partial amides of clodronic acid were synthesized and evaluated in vitro for their properties as bioreversible prodrugs of clodronate. The hydrolysis studies indicated that these derivatives release the parent drug via chemical hydrolysis. Monoamides were hydrolysed rapidly ( t 1/2=16–19 min at pH 7.4) to clodronic acid, which suggests that they are useful intermediates in the design of enzymatically labile double prodrugs of clodronate.

Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. IV Effects of Osteotropic Estradiol on Bone Mineral Density and Uterine Weight in Ovariectomized Rats

An osteotropic drug delivery system (ODDS) based on the bisphosphonic prodrug was designed for 17β-estradiol (E2) in order to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The bisphosphonic prodrug of E2, disodium [17β-(3'-hydroxy-1',3',5'-estratrienyloxy) carbonylpropyl carboxamidomethylene] bisphosphonate (E2-BP) was synthesized and its effects on bone mineral density and uterine weight were investigated in ovariectomized (OVX) rats. E2-BP was injected intravenously once a week (4 injections/experiment), and E2 was administrated orally 5 times a week (20 administrations/experiment). Once a week treatment with 0.1 mg/kg E2-BP significantly restored bone mineral reduction by 61.8% without significantly increasing uterine weight. Similarly, once in 4 weeks treatment with 1.0 mg/kg E2-BP (1 injection/experiment) showed almost the same therapeutic effects. On the other hand, 5 times a week oral treatment with 1.0 mg/kg E2 significantly improved bone mineral density by 90.5%, but increased uterine weight up to 98.2% of that of the sham group. In vitro bone resorption analysis revealed that E2-BP exhibits antiresorptive activity not as a bisphosphonate but as a prodrug of E2. These results demonstrated that E2-BP has the potential to improve patient compliance in estrogen therapy by its minimal adverse effects and less frequent medication.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. V. Biological disposition and targeting characteristics of osteotropic estradiol.

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed for 17 beta-estradiol (E2) to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The biological disposition and the targeting efficiency of a bisphosphonic prodrug of E2, disodium [17 beta-(3'-hydroxy-1',3',5'-estratrienyloxy)carbonylpropyl carboxamidomethylene]bisphosphonate (E2-BP), was investigated in ovariectomized rats. After intravenous injection, E2-BP was rapidly taken up into the bone and subsequently cleared from the bone at a half-life of 13.5 d. The bone concentration of regenerated E2 was maintained throughout 28 d. In contrast, E2 injected intravenously showed extremely low bone distribution and rapid clearance from the bone, and E2 administered orally showed even lower bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for E2 in the bone and plasma after injection of E2-BP and E2, were 64.6 and 451, respectively. These results suggest that ODDS has a potential to improve not only the apparent potency but also the therapeutic index of E2. As compared with the conventional estrogenic products, E2-BP should improve patient compliance with lower adverse effects and less frequent medication in long-term estrogen replacement therapy.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. III: Pharmacokinetics and targeting characteristics of osteotropic carboxyfluorescein.

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. The pharmacokinetics and the targeting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF), disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP), was investigated in rats. After intravenous injection, CF-BP was rapidly taken up into the skeleton, and subsequently cleared from the bone by hydrolysis of its ester linkage at a half-life of 3.2 days. On the other hand, the bone concentration of regenerated CF gradually increased to reach the maximum at 14 days and slowly decreased up to 56 days. Kinetical analysis revealed that bone tissue acts as a reservoir of regenerated CF to supply the parent compound into the systemic circulation. In contrast with CF-BP, CF injected intravenously showed rapid clearance from the plasma and extremely low bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for CF in the bone and plasma after injection of CF-BP and CF, were 1551 and 6689, respectively. These results suggest that ODDS has a potential to improve not only apparent potency but also therapeutic index of the drugs which exhibit their pharmacological effects in the bone.

Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. I: Synthesis and in Vivo Characterization of Osteotropic Carboxyfluorescein

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug was designed as a novel method for site-specific and controlled delivery of drugs to the bone. Due to the chemical adsorption of bisphosphonic promoiety to the mineral component, hydroxyapatite, a bisphosphonic prodrug is predominantly taken up into the bone. To verify the concept, bisphosphonic promoiety was chemically introduced into 6-carboxyfluorescein (CF) as a model compound and the disposition after intravenous injection was studied in rats. The bisphosphonic prodrug of CF, disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP) was highly taken up to the skeleton (62.1% of dose) and the remainder was excreted into the urine (35.9% of dose). Subsequently, regeneration of CF by hydrolysis of CF-BP in the bone was observed. The microscopic observation showed that CF-BP was buried into the bone with a calcification of the bone. According to the remodeling of the bone, bisphosphonic prodrug buried was supposed to be released in the vicinity of the osteoclast or resorption surface of the bone. Thus, it is suggested that ODDS has a potential to achieve osteoclast-specific or resorption surface-specific targeting of the drugs.