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At least 19 recordsLinked to original sources
PubMedDate not supplied

Cytotoxic activity of benzothiepins against human oral tumor cell lines.

A total of 11 newly synthesized benzothiepins and structurally-related compounds were investigated for cytotoxic activity against both normal and tumor cells. All these compounds showed higher cytotoxic activity against three human oral tumor cell lines (HSC-2, HSC-3, HSG) than against normal human gingival fibroblast (HGF), suggesting tumor-specific cytotoxic action. In general, 3,4-dihydro-1-benzothiepin-5(2H)-ones [1-6] showed higher cytotoxic activity than 2,3-dihydro-1-benzothiepins [7-11]. Compounds 4 (4-bromo-3,4-dihydro-2-(2-oxo-2-phenylethyl)-1-benzothiepin-5(2H)-one), 5 (4-bromo-3,4-dihydro-2-(2-oxopropyl)-1-benzothiepin-5(2H)-one) and 6 (4-bromo-3,4-dihydro-2-[1-(methoxycarbonyl)-1-methylethyl]-1-benzothiepin-5(2H)-one), showed higher cytotoxic activity than compounds 1, 2 and 3, respectively, which had Cl instead of Br at C-4 position. Agarose gel electrophoresis demonstrated that these compounds induced large DNA fragments in oral tumor cells, whereas they produced smear pattern of smaller DNA fragments in human promyelocytic leukemia cells HL-60. These data suggest the medicinal efficacy of benzothiepins.

Antineoplastic Agents↗
PubMed1999

Synthesis of novel 2-benzothiopyran and 3-benzothiepin derivatives and their stimulatory effect on bone formation.

In a search for therapeutic agents for the treatment of osteoporosis and bone fracture, we found that 2-benzothiopyran-1-carboxamide derivatives 1, derived from ipriflavone as a lead compound, increase cellular alkaline phosphatase activity in cultures of rat bone marrow stromal cells. Further modification of 1 has led to the discovery of more potent 3-benzothiepin-2-carboxamide derivatives 2. Of these, 3-benzothiepin derivatives bearing a 4-(dialkoxyphosphorylmethyl)phenyl group on the 2-carboxamide moiety such as 2h and 2q exhibited significant improvement of activity compared to ipriflavone. Asymmetric synthesis of 2h and 2q revealed that the (-)-isomers possessed activities superior to those of the (+)-isomers. Further evaluation of these compounds using the mouse osteoblastic cell line MC3T3-E1 revealed that (-)-2q enhanced the effect of bone morphogenetic protein. In addition, application of a sustained-release agent containing 2q increased the area of newly formed bone in a rat skull defect model. Based on these findings, (-)-2q was selected for further investigation as a new drug stimulating bone formation. Synthesis and structure-activity relationships for this novel series of 2-benzothiopyran and 3-benzothiepin derivatives are detailed.

3T3 Cells↗
PubMed2004

Synthesis of 1-benzothiepine and 1-benzazepine derivatives as orally active CCR5 antagonists.

Quaternary ammonium benzocycloheptene compound 1 has previously been reported as a clinical candidate for an injectable CCR5 antagonist. In order to develop an orally active CCR5 antagonist, derivatives of tertiary amine benzocycloheptene 2, the chemical precursor to 1, were investigated. The benzocycloheptene ring was converted to benzothiepine and benzazepine rings and it was found that these changes could enhance the potency of tertiary amine derivatives. In particular, the 1-benzothiepine-1,1-dioxide 11b and the N-methyl-1-benzazepine 18 showed increased activity and good preliminary pharmacokinetic properties. The synthesis of 1-benzothiepine and 1-benzazepine derivatives and their activity are described.

Animals↗
PubMed2004

Orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activity of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives containing a tertiary amine moiety.

The search for orally active CCR5 antagonists was performed by chemical modification of the 1-benzothiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compounds containing a tertiary amine moiety. Replacement of methyl group with a 2-(C(2-4) alkoxy)ethoxy group at the 4-position on the 7-phenyl group of the 1-benzothiepine ring resulted in both enhanced activity and significant improvement in the pharmacokinetic properties upon oral administration in rats. Introduction of C(2-4) alkyl, phenyl or (hetero)arylmethyl groups as the 1-substituent on the 1-benzazepine ring together with the 2-(butoxy)ethoxy group led to further increase of activity. Among the 1-benzazepine derivatives, the isobutyl (6i), benzyl (6o) or 1-methylpyrazol-4-ylmethyl (6s) compounds were found to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activity (IC(50)=2.7 nM) and inhibitory effect (IC(50)=1.2 nM) on membrane fusion, together with good pharmacokinetic properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives and their biological activity are described.

Administration, Oral↗
PubMed1999

TAK-778, a novel synthetic 3-benzothiepin derivative, promotes chondrogenesis in vitro and in vivo.

TAK-778, a novel synthetic 3-benzothiepin derivative, stimulates the formation of cartilaginous nodules in mouse chondroprogenitor-like ATDC5 cells in vitro in association with upregulation of the gene expression of transforming growth factor-beta(2), but not bone morphogenetic protein-4 and insulin-like growth factor-I. One-shot injection of the TAK-778-containing sustained-release microcapsules accelerated the repair process of the full thickness defects of articular cartilage in rabbit knees. Our in vitro and in vivo results indicate that TAK-778 may be a therapeutically useful synthetic agent for articular cartilage repair.

Animals↗
PubMed2004

KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] enhances A-type K+ currents in neurons of the dorsal root ganglion of the adult rat.

Recent studies revealed that a new compound, KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide], can depress the excitability of afferent pathways from the urinary bladder and reduce bladder overactivity induced by chemical irritation of the urinary tract with xylene, an agent that sensitizes capsaicin-sensitive, C-fiber afferent nerves. In the present experiments, we examined the mechanisms that might underlie the depressant effect of KW-7158 on primary afferent neurons by studying the actions of the compound on ion channels and firing in dissociated dorsal root ganglion (DRG) cells from adult rats using whole cell patch-clamp techniques. KW-7158 increased transient, A-type K+ currents at concentrations ranging from 50 nM to 1 microM (20-50% increases). Similar effects were seen in fast blue identified bladder afferent neurons. Low concentrations of KW-7158 shortened the action potential duration, produced a 5- to 10-mV hyperpolarization, and inhibited repetitive firing induced by either 4-AP (50 microM) or substance P (0.5 microM) in phasic firing DRG neurons. Above 1 microM, KW-7158 elicited a smaller enhancement of A-type K+currents and in high concentrations inhibited the currents. Tetraethylammonium (5-60 mM) and verapamil (50 microM), which block noninactivating K+ currents, did not prevent the facilitatory effects of KW-7158. High concentrations of 4-AP (5 mM) inhibited A-type K+ currents and prevented the facilitatory effect of KW-7158 on the remaining currents. These data suggest that KW-7158 enhances A-type K+ currents in DRG neurons. Because A-type K+ channels regulate afferent neuron excitability and firing properties, KW-7158 is a promising new compound for treatment of hyper-reflexic bladder conditions.

4-Aminopyridine↗
PubMed2000

A highly enantioselective benzothiepine synthesis

A highly enantioselective synthesis of benzothiepine 1a has been accomplished via an enantioenriched sulfoxide intermediate obtained by asymmetric oxidation with a chiral oxaziridine in 89:11 er. The key step is a thermodynamically controlled asymmetric cyclization reaction that produces two new stereogenic centers. The (4R,5R) isomer 1a was obtained in 98:2 er.

Journal Article↗
PubMed2002

1-[4-[4[(4R,5R)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octane methanesulfonate (SC-435), an ileal apical sodium-codependent bile acid transporter inhibitor alters hepatic cholesterol metabolism and lowers plasma low-density lipoprotein-cholesterol concentrations in guinea pigs.

Male Hartley guinea pigs (10/group) were assigned either to a control diet (no drug treatment) or to diets containing 0.4, 2.2, or 7.3 mg/day of an ileal apical sodium-codependent bile acid transporter (ASBT) inhibitor, 1-[4-[4[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2] octane methanesulfonate (SC-435). Based on food consumption, guinea pigs received 0, 0.8, 3.7, or 13.4 mg/kg/day of the ASBT inhibitor. The amount of cholesterol in the four diets was maintained at 0.17%, equivalent to 1200 mg/day in the human situation. Guinea pigs treated with 13.4 mg/kg/day SC-435 had 41% lower total cholesterol and 44% lower low-density lipoprotein (LDL)-cholesterol concentrations compared with control (P < 0.01), whereas no significant differences were observed with either of the lower doses of SC-435. Hepatic cholesterol esters were significantly reduced by 43, 56, and 70% in guinea pigs fed 0.8, 3.7, and 13.4 mg/kg/day of the ASBT inhibitor, respectively (P < 0.01). In addition, the highest dose of the inhibitor resulted in a 42% increase in the number of very low-density lipoprotein (VLDL) triacylglycerol molecules and a larger VLDL diameter compared with controls (P < 0.05). Acyl-CoA cholesterol/acyltransferase activity was 30% lower with the highest dose treatment, whereas cholesterol 7alpha-hydroxylase, the regulatory enzyme of bile acid synthesis, was 30% higher with the highest ASBT inhibitor dose (P < 0.05). Furthermore, bile acid excretion increased 2-fold with the highest dose of SC-435 compared with the control group (P < 0.05). These results suggest that the reduction in total and LDL-cholesterol concentrations by the ASBT inhibitor is a result of alterations in hepatic cholesterol metabolism due to modifications in the enterohepatic circulation of bile acids.

Animals↗
PubMed2005

Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 1).

Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14 cells. A 3R,4R,5R/3S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.

Animals↗
PubMed2001

Sustained-release microcapsules of a bone formation stimulant, TAK-778, for local injection into a fracture site.

The benzothiepin derivative (2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (TAK-778) is a potent bone formation stimulant. A sustained release formulation was prepared by encapsulating the drug into biodegradable microcapsules for local application to fracture repair in rats. The microcapsules consisted of TAK-778 (10% w/w) and a biodegradable polymer, copoly (d,l-lactic/glycolic acid), with a copolymer ratio of 85:15 (mol/mol) and an average molecular weight of 15 k. The TAK-778 amount at the injection site progressively diminished for 4 weeks after administration, and the serum level of TAK-778 was sustained over the same period. The local concentration of TAK-778 after administration of the microcapsules was simulated by a two-compartment open model. In the model, a first-order release rate constant and a transfer rate constant were obtained from the release profile of the microcapsules and the serum level of TAK-778 after administration of the TAK-778 solution, respectively. Localization at the injection site was examined by radiography using microcapsules in which iodoform was encapsulated as a contrast agent. The microcapsules formed a clot at the injection site, and their spread was narrowly restricted. The local concentration was calculated to be maintained within the range 10(-3)-10(-6) M over 4 weeks on the assumption that the dose and spread volume were 5 mg of TAK-778/site and 3 mL, respectively.

Animals↗
PubMed2005

Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 2).

In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.

Absorption↗
PubMed2000

Enhancement of fracture repair in rats with streptozotocin-induced diabetes by a single injection of biodegradable microcapsules containing a bone formation stimulant, TAK-778.

The feasibility of using microcapsules containing a bone formation stimulant, (2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4, 5-tetrahydro-4-methyl-7, 8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (TAK-778) to enhance fracture repair was assessed in rats with streptozotocin-induced diabetes. The release profile of the microcapsules was designed to mimic a dosing regimen of multiple injections of TAK-778 solution. The solution was injected locally every third day from day 0 (the day of operation) to day 27 according to several dosing regimens, and fracture repair was assessed at day 28. The production of callus was most prominent when TAK-778 solution was injected so that 50-75% of the total dose (5 mg TAK-778/site) was administered during the first half of the treatment period. Thus, injectable microcapsules of 30 micrometer in mean diameter were prepared in order to release TAK-778 over 4 weeks using a biodegradable polymer, poly(d,l-lactic/glycolic) acid, with a copolymer ratio of 85:15 (mol/mol) and an average molecular weight of 14,000. A single local injection of the microcapsules markedly enhanced fracture repair, which resulted in recovery of destructive bending strength of the bone at day 28. Histologically, the injection of TAK-778 microcapsules stimulated both fibrous and cartilaginous proliferation and periosteal ossification in the callus at day 7; bony bridge formation was observed at day 28. At day 56, the callus was remodeled and cortical bony union was evidenced in the microcapsule-treated fractures compared with the controls, which showed only fibrous union.

Animals↗
PubMed2001

Bone bonding in sintered hydroxyapatite combined with a new synthesized agent, TAK-778.

We studied the stimulatory effects of TAK-778, a new synthetic 3-benzothiepin derivative that promotes osteoblast differentiation, in bone bonding to sintered hydroxyapatite implants in rabbit tibiae. Smooth-surfaced rectangular plates (15 x 10 x 2 mm) made of sintered hydroxyapatite were implanted into the proximal metaphyses of bilateral rabbit tibiae, with TAK-778-containing sustained-release microcapsules packed into the medullary cavity in one limb and untreated microcapsules packed in the contralateral limb to serve as a paired control. At 4, 8, and 16 weeks after implantation, bone bonding at the bone-implant interfaces was evaluated by a detaching test and undecalcified histological examination. The tensile failure load increased from 4 to 16 weeks for both groups; however, the tensile failure load of the TAK-778-treated group was significantly greater than that of the control group at each interval after implantation. Histologically, the TAK-778-treated specimens showed greater active new bone formation mainly in the medullary cavity and more extensive bonding between the implant and bone than the untreated specimens. The results of this study suggest that adding osteoinductive TAK-778 to hydroxyapatite implants may significantly accelerate bone apposition to the implants and improve the bonding process at the interface. This would help to establish an earlier and stronger bonding of orthopedic ceramic implants between the surrounding bone tissue.

Absorbable Implants↗
PubMed2001

Bone bonding in bioactive glass ceramics combined with a new synthesized agent TAK-778.

We studied the stimulatory effects of TAK-778, a new synthetic 3-benzothiepin derivative that promotes osteoblast differentiation, in the bonding of bone to bioactive glass ceramic implants in rabbit tibiae. Smooth-surfaced, rectangular plates (15 x 10 x 2 mm) made of apatite-wollastonite-containing glass ceramic were implanted bilaterally into the proximal metaphyses of rabbit tibiae. Sustained-release microcapsules containing TAK-778 were packed into the medullary cavity in one limb and untreated microcapsules were packed into the contralateral limb to serve as a paired control. At 4, 8, and 16 weeks after implantation, bonding at the bone/implant interfaces was evaluated using a detaching test and histological examination of undecalcified specimens. The tensile failure load increased during weeks 4 to 16 in both groups; the tensile failure load in the TAK-778-treated group was significantly greater than that in the control group at each interval after implantation. Histologically, the TAK-778-treated specimens showed greater active new bone formation mainly in the medullary cavity and more extensive bonding between the implant and bone than the untreated specimens. The results of this study suggest that adding the bone formation-promoting TAK-778 to bioactive glass ceramic implants may significantly accelerate bone apposition to the implants and improve the bonding process at the interface. This would help to establish earlier and stronger bonding of orthopedic ceramic implants to the surrounding bone tissue.

Animals↗